modeling_fast_esmfold.py

from __future__ import annotations

import torch
import torch._inductor.config as inductor_config
import torch._dynamo as dynamo

# Enable TensorFloat32 tensor cores for float32 matmul (Ampere+ GPUs)
# Provides significant speedup with minimal precision loss
torch.set_float32_matmul_precision('high')

# Enable TF32 for matrix multiplications and cuDNN operations
torch.backends.cuda.matmul.allow_tf32 = True
torch.backends.cudnn.allow_tf32 = True

# Enable cuDNN autotuner - finds fastest algorithms for your hardware
# Best when input sizes are consistent; may slow down first iterations
torch.backends.cudnn.benchmark = True

# Deterministic operations off for speed (set True if reproducibility needed)
torch.backends.cudnn.deterministic = False
inductor_config.max_autotune_gemm_backends = "ATEN,CUTLASS,FBGEMM"    

dynamo.config.capture_scalar_outputs = True
torch._dynamo.config.recompile_limit = 16

"""Shared attention infrastructure for all FastPLMs models.

Contains: AttentionBackend enum, backend resolution, mask creation,
flex attention helpers, flash kernel detection/dispatch, and pad/unpad utilities.
"""
from enum import Enum
from typing import Dict, List, Optional, Tuple

import torch
import torch.nn as nn
from torch.nn import functional as F
from einops import rearrange

try:
    from torch.nn.attention.flex_attention import create_block_mask, flex_attention, BlockMask
except ImportError:
    create_block_mask = None
    flex_attention = None
    BlockMask = None

_compiled_flex_attention = None


def _get_flex_attention_fn():
    """Return flex_attention callable: compiled (fused kernel) by default, or eager when debug flag is set."""
    global _compiled_flex_attention
    if flex_attention is None:
        return None
    flex_mod = torch.nn.attention.flex_attention
    if getattr(flex_mod, "_FLEX_ATTENTION_DISABLE_COMPILE_DEBUG", False):
        return flex_attention
    if _compiled_flex_attention is None:
        _compiled_flex_attention = torch.compile(
            flex_attention,
            dynamic=False,
        )
    return _compiled_flex_attention


### Kernels Flash Attention Detection
def _infer_kernels_flash_variant(kernel) -> Optional[str]:
    if hasattr(kernel, "fwd") and hasattr(kernel, "varlen_fwd"):
        return "flash_attn2"
    if hasattr(kernel, "flash_attn_func") and hasattr(kernel, "flash_attn_varlen_func"):
        return "flash_attn3"
    return None


def _try_get_kernels_flash():
    try:
        from kernels import get_kernel
    except ImportError:
        return None, None

    flash_kernel = None
    flash_kernel_variant = None
    try:
        flash_kernel = get_kernel("kernels-community/flash-attn3")
        flash_kernel_variant = _infer_kernels_flash_variant(flash_kernel)
        assert flash_kernel_variant is not None, "Loaded flash-attn3 kernel does not expose a supported API."
    except Exception:
        try:
            flash_kernel = get_kernel("kernels-community/flash-attn2")
            flash_kernel_variant = _infer_kernels_flash_variant(flash_kernel)
            assert flash_kernel_variant is not None, "Loaded flash-attn2 kernel does not expose a supported API."
        except Exception:
            flash_kernel = None
            flash_kernel_variant = None
    return flash_kernel, flash_kernel_variant


_FLASH_KERNELS_LOADED = False
FLASH_KERNEL = None
FLASH_KERNEL_VARIANT = None


def _ensure_flash_kernels_loaded():
    global _FLASH_KERNELS_LOADED, FLASH_KERNEL, FLASH_KERNEL_VARIANT
    if _FLASH_KERNELS_LOADED:
        return
    _FLASH_KERNELS_LOADED = True
    FLASH_KERNEL, FLASH_KERNEL_VARIANT = _try_get_kernels_flash()


def _kernels_flash_forward(
    query_states: torch.Tensor,
    key_states: torch.Tensor,
    value_states: torch.Tensor,
    causal: bool = False,
) -> torch.Tensor:
    assert FLASH_KERNEL is not None, "Kernel Flash Attention is not available in this environment."
    if FLASH_KERNEL_VARIANT == "flash_attn2":
        return FLASH_KERNEL.fwd(q=query_states, k=key_states, v=value_states, is_causal=causal)[0]
    if FLASH_KERNEL_VARIANT == "flash_attn3":
        try:
            output = FLASH_KERNEL.flash_attn_func(q=query_states, k=key_states, v=value_states, causal=causal)
        except TypeError:
            output = FLASH_KERNEL.flash_attn_func(query_states, key_states, value_states, 0.0, None, causal)
        if isinstance(output, tuple):
            return output[0]
        return output
    raise AssertionError(f"Unsupported kernels flash attention variant: {FLASH_KERNEL_VARIANT}")


def _kernels_flash_varlen_forward(
    query_states: torch.Tensor,
    key_states: torch.Tensor,
    value_states: torch.Tensor,
    cu_seqlens_q: torch.Tensor,
    cu_seqlens_k: torch.Tensor,
    max_seqlen_in_batch_q: int,
    max_seqlen_in_batch_k: int,
    causal: bool = False,
) -> torch.Tensor:
    assert FLASH_KERNEL is not None, "Kernel Flash Attention is not available in this environment."
    if FLASH_KERNEL_VARIANT == "flash_attn2":
        return FLASH_KERNEL.varlen_fwd(
            q=query_states, k=key_states, v=value_states,
            cu_seqlens_q=cu_seqlens_q, cu_seqlens_k=cu_seqlens_k,
            max_seqlen_q=max_seqlen_in_batch_q, max_seqlen_k=max_seqlen_in_batch_k,
            is_causal=causal,
        )[0]
    if FLASH_KERNEL_VARIANT == "flash_attn3":
        try:
            output = FLASH_KERNEL.flash_attn_varlen_func(
                q=query_states, k=key_states, v=value_states,
                cu_seqlens_q=cu_seqlens_q, cu_seqlens_k=cu_seqlens_k,
                max_seqlen_q=max_seqlen_in_batch_q, max_seqlen_k=max_seqlen_in_batch_k,
                causal=causal,
            )
        except TypeError:
            output = FLASH_KERNEL.flash_attn_varlen_func(
                query_states, key_states, value_states,
                cu_seqlens_q, cu_seqlens_k,
                max_seqlen_in_batch_q, max_seqlen_in_batch_k,
                0.0, None, causal,
            )
        if isinstance(output, tuple):
            return output[0]
        return output
    raise AssertionError(f"Unsupported kernels flash attention variant: {FLASH_KERNEL_VARIANT}")


### Unpad / Pad helpers for varlen flash attention
class IndexFirstAxis(torch.autograd.Function):
    @staticmethod
    def forward(ctx, input, indices) -> torch.Tensor:
        ctx.save_for_backward(indices)
        assert input.ndim >= 2
        ctx.first_axis_dim, other_shape = input.shape[0], input.shape[1:]
        second_dim = other_shape.numel()
        return torch.gather(
            rearrange(input, "b ... -> b (...)"), 0, indices.unsqueeze(1).expand(-1, second_dim)
        ).reshape(-1, *other_shape)

    @staticmethod
    def backward(ctx, grad_output) -> Tuple[torch.Tensor, None]:
        (indices,) = ctx.saved_tensors
        assert grad_output.ndim >= 2
        other_shape = grad_output.shape[1:]
        grad_output = rearrange(grad_output, "b ... -> b (...)")
        grad_input = torch.zeros(
            [ctx.first_axis_dim, grad_output.shape[1]], device=grad_output.device, dtype=grad_output.dtype
        )
        grad_input.scatter_(0, indices.unsqueeze(1).expand(-1, grad_output.shape[1]), grad_output)
        return grad_input.reshape(ctx.first_axis_dim, *other_shape), None


class IndexPutFirstAxis(torch.autograd.Function):
    @staticmethod
    def forward(ctx, values, indices, first_axis_dim) -> torch.Tensor:
        ctx.save_for_backward(indices)
        assert indices.ndim == 1
        assert values.ndim >= 2
        output = torch.zeros(first_axis_dim, *values.shape[1:], device=values.device, dtype=values.dtype)
        output[indices] = values
        return output

    @staticmethod
    def backward(ctx, grad_output) -> Tuple[torch.Tensor, None, None]:
        (indices,) = ctx.saved_tensors
        return grad_output[indices], None, None


index_first_axis = IndexFirstAxis.apply
index_put_first_axis = IndexPutFirstAxis.apply


def pad_input(hidden_states: torch.Tensor, indices: torch.Tensor, batch: int, seqlen: int) -> torch.Tensor:
    output = index_put_first_axis(hidden_states, indices, batch * seqlen)
    return rearrange(output, "(b s) ... -> b s ...", b=batch)


def _unpad_input(
    query_layer: torch.Tensor,
    key_layer: torch.Tensor,
    value_layer: torch.Tensor,
    attention_mask_2d: torch.Tensor,
) -> Tuple[torch.Tensor, torch.Tensor, torch.Tensor, torch.Tensor, Tuple[torch.Tensor, torch.Tensor], Tuple[int, int]]:
    batch_size, seq_len, num_heads, head_dim = query_layer.shape
    seqlens = attention_mask_2d.sum(dim=1).int()
    cu_seqlens = F.pad(seqlens.cumsum(0, dtype=torch.int32), (1, 0))
    max_seqlen = int(seqlens.max().item())
    indices = attention_mask_2d.flatten().nonzero(as_tuple=False).flatten()
    query_layer = index_first_axis(query_layer.reshape(batch_size * seq_len, num_heads, head_dim), indices)
    key_layer = index_first_axis(key_layer.reshape(batch_size * seq_len, num_heads, head_dim), indices)
    value_layer = index_first_axis(value_layer.reshape(batch_size * seq_len, num_heads, head_dim), indices)
    return query_layer, key_layer, value_layer, indices, (cu_seqlens, cu_seqlens), (max_seqlen, max_seqlen)


def kernels_flash_attention_func(
    query_states: torch.Tensor,
    key_states: torch.Tensor,
    value_states: torch.Tensor,
    attention_mask_2d: Optional[torch.Tensor] = None,
    causal: bool = False,
) -> torch.Tensor:
    assert FLASH_KERNEL is not None, "Kernel Flash Attention is not available in this environment."
    if not causal and attention_mask_2d is not None:
        batch_size, q_len = query_states.shape[:2]
        (
            query_states, key_states, value_states,
            indices_q, (cu_seqlens_q, cu_seqlens_k), (max_seqlen_q, max_seqlen_k),
        ) = _unpad_input(query_states, key_states, value_states, attention_mask_2d)
        attn_output_unpad = _kernels_flash_varlen_forward(
            query_states=query_states, key_states=key_states, value_states=value_states,
            cu_seqlens_q=cu_seqlens_q, cu_seqlens_k=cu_seqlens_k,
            max_seqlen_in_batch_q=max_seqlen_q, max_seqlen_in_batch_k=max_seqlen_k,
        )
        return pad_input(attn_output_unpad, indices_q, batch_size, q_len)
    else:
        return _kernels_flash_forward(
            query_states=query_states, key_states=key_states, value_states=value_states, causal=causal,
        )


### Attention Backend Enum & Resolution
class AttentionBackend(Enum):
    AUTO = "auto"
    KERNELS_FLASH = "kernels_flash"
    FLEX = "flex"
    SDPA = "sdpa"


VALID_ATTENTION_BACKENDS = tuple(b.value for b in AttentionBackend)


_BACKEND_CONFIRMED = False


def resolve_attention_backend(requested_backend: str) -> AttentionBackend:
    global _BACKEND_CONFIRMED
    assert requested_backend in VALID_ATTENTION_BACKENDS, (
        f"Unsupported attention backend: {requested_backend}. Expected one of {VALID_ATTENTION_BACKENDS}."
    )
    if requested_backend in (AttentionBackend.AUTO.value, AttentionBackend.KERNELS_FLASH.value):
        _ensure_flash_kernels_loaded()
    if requested_backend == AttentionBackend.AUTO.value:
        if FLASH_KERNEL is not None:
            resolved = AttentionBackend.KERNELS_FLASH
        elif flex_attention is not None:
            resolved = AttentionBackend.FLEX
        else:
            resolved = AttentionBackend.SDPA
    elif requested_backend == AttentionBackend.KERNELS_FLASH.value:
        assert FLASH_KERNEL is not None, "Kernels Flash Attention is not available in this environment."
        resolved = AttentionBackend.KERNELS_FLASH
    elif requested_backend == AttentionBackend.FLEX.value:
        assert flex_attention is not None, "Flex Attention is not available in this environment."
        resolved = AttentionBackend.FLEX
    elif requested_backend == AttentionBackend.SDPA.value:
        resolved = AttentionBackend.SDPA
    else:
        raise AssertionError(f"Unsupported attention backend: {requested_backend}")
    if not _BACKEND_CONFIRMED:
        print(f"Attention backend: config='{requested_backend}' -> resolved='{resolved.value}'")
        _BACKEND_CONFIRMED = True
    return resolved


@torch.compiler.disable
def get_attention_mask(
    effective_backend: AttentionBackend,
    batch_size: int,
    seq_len: int,
    device: torch.device,
    attention_mask: Optional[torch.Tensor] = None,
) -> Tuple[Optional[torch.Tensor], Optional[torch.Tensor], Optional[BlockMask]]:
    """Build padding masks once for all encoder layers.

    Returns (attention_mask_2d, attention_mask_4d, flex_block_mask).
    """
    if attention_mask is None:
        return None, None, None

    attention_mask_2d = attention_mask.bool()

    if effective_backend == AttentionBackend.KERNELS_FLASH:
        return attention_mask_2d, None, None

    if effective_backend == AttentionBackend.FLEX:
        assert create_block_mask is not None, "Flex attention backend requested but torch.create_block_mask is unavailable."
        valid_lens = attention_mask_2d.sum(dim=-1)

        def mask_mod(batch_idx, head_idx, q_idx, kv_idx):
            return (q_idx < valid_lens[batch_idx]) & (kv_idx < valid_lens[batch_idx])

        flex_block_mask = create_block_mask(mask_mod, batch_size, 1, seq_len, seq_len, device=device)
        return attention_mask_2d, None, flex_block_mask

    # SDPA / manual -- only mask the key dimension so padding query positions attend to
    # real keys and produce valid (non-NaN) outputs instead of NaN from softmax(-inf,...,-inf).
    attention_mask_4d = attention_mask_2d[:, None, None, :]
    return attention_mask_2d, attention_mask_4d, None

"""FastESMFold: Self-contained ESMFold with FastESM2 attention backends + built-in Test-Time Training.

Usage:
    from transformers import AutoModel
    model = AutoModel.from_pretrained("Synthyra/FastESMFold", trust_remote_code=True).cuda()

    # Basic folding
    result = model.fold_protein("MKTLLILAVVA...")
    print(result["plddt"], result["pdb_string"][:100])

    # Folding with TTT (test-time training improves structure prediction)
    result = model.fold_protein("MKTLLILAVVA...", ttt=True)

Dependencies: torch, transformers, einops, peft (for LoRA TTT only)
No dependency on: esm (fair-esm), proteinttt, openfold
"""
import copy
from dataclasses import dataclass, field
from functools import wraps
from typing import Any, Callable, Dict, List, Optional, Tuple, Union

import torch
import torch.nn as nn
from torch.nn import functional as F

from einops import rearrange
from transformers import EsmTokenizer, PretrainedConfig, PreTrainedModel
from transformers.modeling_outputs import ModelOutput
from transformers.models.esm.configuration_esm import EsmConfig
from transformers.models.esm.modeling_esm import (
    EsmContactPredictionHead,
    EsmEmbeddings,
    EsmIntermediate,
    EsmLMHead,
    EsmOutput,
    EsmSelfOutput,
    RotaryEmbedding,
)
from transformers.models.esm.modeling_esmfold import EsmForProteinFolding




# =============================================================================
# Output Dataclass
# =============================================================================

@dataclass
class FastEsmEncoderOutput(ModelOutput):
    last_hidden_state: Optional[torch.Tensor] = None
    hidden_states: Optional[Tuple[torch.Tensor, ...]] = None
    attentions: Optional[Tuple[torch.Tensor, ...]] = None


# =============================================================================
# FastESM2 Attention Layers (multi-backend: SDPA, Flash, Flex)
# =============================================================================

class EsmSelfAttention(nn.Module):
    def __init__(self, config, position_embedding_type: Optional[str] = None):
        super().__init__()
        assert config.hidden_size % config.num_attention_heads == 0, (
            f"The hidden size ({config.hidden_size}) is not a multiple of the number of attention "
            f"heads ({config.num_attention_heads})"
        )
        self.num_attention_heads = config.num_attention_heads
        self.attention_head_size = int(config.hidden_size / config.num_attention_heads)
        self.all_head_size = self.num_attention_heads * self.attention_head_size

        self.query = nn.Linear(config.hidden_size, self.all_head_size)
        self.key = nn.Linear(config.hidden_size, self.all_head_size)
        self.value = nn.Linear(config.hidden_size, self.all_head_size)
        self.scale = self.attention_head_size**-0.5

        self.dropout_prob = config.attention_probs_dropout_prob
        self.config = config
        self.attn_backend = resolve_attention_backend(config.attn_backend)
        self.position_embedding_type = position_embedding_type or config.position_embedding_type
        self.rotary_embeddings = None
        if self.position_embedding_type == "rotary":
            self.rotary_embeddings = RotaryEmbedding(dim=self.attention_head_size)

    def forward(
        self,
        hidden_states: torch.Tensor,
        attention_mask_2d: Optional[torch.Tensor] = None,
        attention_mask_4d: Optional[torch.Tensor] = None,
        flex_block_mask: Optional[BlockMask] = None,
        output_attentions: bool = False,
    ) -> Tuple[torch.Tensor, Optional[torch.Tensor]]:
        batch_size, seq_length = hidden_states.shape[:-1]
        hidden_shape = (batch_size, seq_length, -1, self.attention_head_size)
        query_BHLD = self.query(hidden_states).view(hidden_shape).transpose(1, 2)
        key_BHLD = self.key(hidden_states).view(hidden_shape).transpose(1, 2)
        value_BHLD = self.value(hidden_states).view(hidden_shape).transpose(1, 2)

        query_BHLD = query_BHLD * self.scale

        if self.position_embedding_type == "rotary":
            query_BHLD, key_BHLD = self.rotary_embeddings(query_BHLD, key_BHLD)

        attn_output, attn_weights = self._attn(
            query_BHLD, key_BHLD, value_BHLD,
            attention_mask_2d=attention_mask_2d,
            attention_mask_4d=attention_mask_4d,
            flex_block_mask=flex_block_mask,
            output_attentions=output_attentions,
        )
        return attn_output, attn_weights

    def _attn(
        self,
        query_BHLD: torch.Tensor,
        key_BHLD: torch.Tensor,
        value_BHLD: torch.Tensor,
        attention_mask_2d: Optional[torch.Tensor] = None,
        attention_mask_4d: Optional[torch.Tensor] = None,
        flex_block_mask: Optional[BlockMask] = None,
        output_attentions: bool = False,
    ) -> Tuple[torch.Tensor, Optional[torch.Tensor]]:
        if output_attentions:
            return self._manual_attn(query_BHLD, key_BHLD, value_BHLD, attention_mask_4d)

        if self.attn_backend == AttentionBackend.KERNELS_FLASH:
            return self._kernels_flash_attn(query_BHLD, key_BHLD, value_BHLD, attention_mask_2d)
        elif self.attn_backend == AttentionBackend.FLEX:
            return self._flex_attn(query_BHLD, key_BHLD, value_BHLD, flex_block_mask)
        elif self.attn_backend == AttentionBackend.SDPA:
            return self._sdpa_attn(query_BHLD, key_BHLD, value_BHLD, attention_mask_4d)
        else:
            raise AssertionError(f"Unsupported resolved backend: {self.attn_backend}")

    def _manual_attn(
        self,
        query_BHLD: torch.Tensor,
        key_BHLD: torch.Tensor,
        value_BHLD: torch.Tensor,
        attention_mask_4d: Optional[torch.Tensor] = None,
    ) -> Tuple[torch.Tensor, torch.Tensor]:
        attn_weights = torch.matmul(query_BHLD, key_BHLD.transpose(-1, -2))
        if attention_mask_4d is not None:
            attn_weights = attn_weights.masked_fill(attention_mask_4d.logical_not(), float("-inf"))
        attn_weights = F.softmax(attn_weights, dim=-1)
        if self.dropout_prob > 0 and self.training:
            attn_weights = F.dropout(attn_weights, p=self.dropout_prob, training=self.training)
        context_BHLD = torch.matmul(attn_weights, value_BHLD)
        attn_output = rearrange(context_BHLD, "b h s d -> b s (h d)")
        return attn_output, attn_weights

    def _kernels_flash_attn(
        self,
        query_BHLD: torch.Tensor,
        key_BHLD: torch.Tensor,
        value_BHLD: torch.Tensor,
        attention_mask_2d: Optional[torch.Tensor] = None,
    ) -> Tuple[torch.Tensor, None]:
        query_BLHD = query_BHLD.transpose(1, 2).contiguous()
        key_BLHD = key_BHLD.transpose(1, 2).contiguous()
        value_BLHD = value_BHLD.transpose(1, 2).contiguous()
        attn_output = kernels_flash_attention_func(
            query_states=query_BLHD, key_states=key_BLHD, value_states=value_BLHD,
            attention_mask_2d=attention_mask_2d, causal=False,
        )
        return rearrange(attn_output, "b s h d -> b s (h d)"), None

    def _flex_attn(
        self,
        query_BHLD: torch.Tensor,
        key_BHLD: torch.Tensor,
        value_BHLD: torch.Tensor,
        flex_block_mask: Optional[BlockMask] = None,
    ) -> Tuple[torch.Tensor, None]:
        assert flex_attention is not None, "Flex attention is not available in this environment."
        fn = _get_flex_attention_fn()
        context_BHLD = fn(query_BHLD, key_BHLD, value_BHLD, block_mask=flex_block_mask, scale=1.0)
        return rearrange(context_BHLD, "b h s d -> b s (h d)"), None

    def _sdpa_attn(
        self,
        query_BHLD: torch.Tensor,
        key_BHLD: torch.Tensor,
        value_BHLD: torch.Tensor,
        attention_mask_4d: Optional[torch.Tensor] = None,
    ) -> Tuple[torch.Tensor, None]:
        context_BHLD = F.scaled_dot_product_attention(
            query_BHLD, key_BHLD, value_BHLD,
            attn_mask=attention_mask_4d,
            dropout_p=self.dropout_prob if self.training else 0.0,
            scale=1.0,
        )
        return rearrange(context_BHLD, "b h s d -> b s (h d)"), None


class EsmAttention(nn.Module):
    def __init__(self, config):
        super().__init__()
        self.self = EsmSelfAttention(config)
        self.output = EsmSelfOutput(config)
        self.LayerNorm = nn.LayerNorm(config.hidden_size, eps=config.layer_norm_eps)

    def forward(
        self,
        hidden_states: torch.Tensor,
        attention_mask_2d: Optional[torch.Tensor] = None,
        attention_mask_4d: Optional[torch.Tensor] = None,
        flex_block_mask: Optional[BlockMask] = None,
        output_attentions: bool = False,
    ) -> Tuple[torch.Tensor, Optional[torch.Tensor]]:
        hidden_states_ln = self.LayerNorm(hidden_states)
        attn_output, attn_weights = self.self(
            hidden_states_ln,
            attention_mask_2d=attention_mask_2d,
            attention_mask_4d=attention_mask_4d,
            flex_block_mask=flex_block_mask,
            output_attentions=output_attentions,
        )
        attention_output = self.output(attn_output, hidden_states)
        return attention_output, attn_weights


class EsmLayer(nn.Module):
    def __init__(self, config):
        super().__init__()
        self.attention = EsmAttention(config)
        self.intermediate = EsmIntermediate(config)
        self.output = EsmOutput(config)
        self.LayerNorm = nn.LayerNorm(config.hidden_size, eps=config.layer_norm_eps)

    def forward(
        self,
        hidden_states: torch.Tensor,
        attention_mask_2d: Optional[torch.Tensor] = None,
        attention_mask_4d: Optional[torch.Tensor] = None,
        flex_block_mask: Optional[BlockMask] = None,
        output_attentions: bool = False,
    ) -> Tuple[torch.Tensor, Optional[torch.Tensor]]:
        attention_output, attn_weights = self.attention(
            hidden_states,
            attention_mask_2d=attention_mask_2d,
            attention_mask_4d=attention_mask_4d,
            flex_block_mask=flex_block_mask,
            output_attentions=output_attentions,
        )
        layer_output = self._feed_forward(attention_output)
        return layer_output, attn_weights

    def _feed_forward(self, attention_output: torch.Tensor) -> torch.Tensor:
        attention_output_ln = self.LayerNorm(attention_output)
        intermediate_output = self.intermediate(attention_output_ln)
        return self.output(intermediate_output, attention_output)


class FastEsmEncoder(nn.Module):
    def __init__(self, config):
        super().__init__()
        self.config = config
        self.attention_backend = resolve_attention_backend(config.attn_backend)
        self.layer = nn.ModuleList([EsmLayer(config) for _ in range(config.num_hidden_layers)])
        self.emb_layer_norm_after = nn.LayerNorm(config.hidden_size, eps=config.layer_norm_eps)

    def forward(
        self,
        hidden_states: torch.Tensor,
        attention_mask: Optional[torch.Tensor] = None,
        output_hidden_states: bool = False,
        output_attentions: bool = False,
    ) -> FastEsmEncoderOutput:
        all_hidden_states = () if output_hidden_states else None
        all_attentions = () if output_attentions else None

        attention_mask_2d, attention_mask_4d, flex_block_mask = get_attention_mask(
            effective_backend=self.attention_backend,
            batch_size=hidden_states.shape[0],
            seq_len=hidden_states.shape[1],
            device=hidden_states.device,
            attention_mask=attention_mask,
        )

        for layer_module in self.layer:
            if output_hidden_states:
                all_hidden_states = all_hidden_states + (hidden_states,)

            hidden_states, attn_weights = layer_module(
                hidden_states,
                attention_mask_2d=attention_mask_2d,
                attention_mask_4d=attention_mask_4d,
                flex_block_mask=flex_block_mask,
                output_attentions=output_attentions,
            )

            if all_attentions is not None:
                all_attentions = all_attentions + (attn_weights,)

        if self.emb_layer_norm_after:
            hidden_states = self.emb_layer_norm_after(hidden_states)

        if output_hidden_states:
            all_hidden_states = all_hidden_states + (hidden_states,)

        return FastEsmEncoderOutput(
            last_hidden_state=hidden_states,
            hidden_states=all_hidden_states,
            attentions=all_attentions,
        )


# =============================================================================
# FastESM Backbone (replaces EsmModel inside ESMFold)
# =============================================================================

class FastEsmBackbone(nn.Module):
    """FastESM2 backbone with multi-backend attention. Drop-in replacement for
    transformers.EsmModel inside EsmForProteinFolding.

    State dict keys match HuggingFace EsmModel exactly, so pretrained weights
    load without any key remapping.
    """

    def __init__(self, config):
        super().__init__()
        self.config = config
        self.embeddings = EsmEmbeddings(config)
        self.encoder = FastEsmEncoder(config)
        self.contact_head = EsmContactPredictionHead(
            in_features=config.num_hidden_layers * config.num_attention_heads, bias=True
        )

    def forward(
        self,
        input_ids: Optional[torch.Tensor] = None,
        attention_mask: Optional[torch.Tensor] = None,
        position_ids: Optional[torch.Tensor] = None,
        inputs_embeds: Optional[torch.Tensor] = None,
        output_attentions: Optional[bool] = None,
        output_hidden_states: Optional[bool] = None,
        return_dict: Optional[bool] = None,
        **kwargs,
    ) -> FastEsmEncoderOutput:
        output_attentions = output_attentions if output_attentions is not None else False
        output_hidden_states = output_hidden_states if output_hidden_states is not None else False

        token_embedding_output = self.embeddings(
            input_ids=input_ids,
            position_ids=position_ids,
            attention_mask=attention_mask,
            inputs_embeds=inputs_embeds,
        )
        encoder_outputs = self.encoder(
            token_embedding_output,
            attention_mask=attention_mask,
            output_hidden_states=output_hidden_states,
            output_attentions=output_attentions,
        )
        return FastEsmEncoderOutput(
            last_hidden_state=encoder_outputs.last_hidden_state,
            hidden_states=encoder_outputs.hidden_states,
            attentions=encoder_outputs.attentions,
        )


# =============================================================================
# TTT (Test-Time Training) Configuration and Utilities
# =============================================================================

_ESM_STANDARD_AA = list("ACDEFGHIKLMNPQRSTVWY")


class LoraInjectedLinear(nn.Module):
    """LoRA-augmented linear layer matching lora_diffusion's behavior.

    Replaces an existing nn.Linear with base(x) + lora_up(lora_down(x)) * scale.
    Initialization follows cloneofsimo/lora: down=Normal(0, 1/r), up=zeros.
    """

    def __init__(self, original_linear: nn.Linear, r: int = 4, scale: float = 1.0):
        super().__init__()
        self.linear = original_linear
        in_features = original_linear.in_features
        out_features = original_linear.out_features
        assert r <= min(in_features, out_features), f"LoRA rank {r} exceeds dimensions ({in_features}, {out_features})"
        self.lora_down = nn.Linear(in_features, r, bias=False)
        self.lora_up = nn.Linear(r, out_features, bias=False)
        self.scale = scale
        nn.init.normal_(self.lora_down.weight, std=1.0 / r)
        nn.init.zeros_(self.lora_up.weight)

    def forward(self, x: torch.Tensor) -> torch.Tensor:
        return self.linear(x) + self.lora_up(self.lora_down(x)) * self.scale


def inject_trainable_lora(
    model: nn.Module,
    target_class_name: str,
    r: int,
    scale: float,
) -> List[nn.Parameter]:
    """Replace nn.Linear layers inside modules matching target_class_name with LoRA.

    Matches lora_diffusion's inject_trainable_lora behavior: finds all modules whose
    class name matches target_class_name, then replaces their nn.Linear children with
    LoraInjectedLinear. Returns the list of trainable LoRA parameters.
    """
    lora_params: List[nn.Parameter] = []
    for _parent_name, parent_module in model.named_modules():
        if parent_module.__class__.__name__ != target_class_name:
            continue
        for child_name, child_module in list(parent_module.named_children()):
            if not isinstance(child_module, nn.Linear):
                continue
            lora_linear = LoraInjectedLinear(child_module, r=r, scale=scale)
            lora_linear = lora_linear.to(
                device=child_module.weight.device,
                dtype=child_module.weight.dtype,
            )
            setattr(parent_module, child_name, lora_linear)
            lora_params.extend(lora_linear.lora_down.parameters())
            lora_params.extend(lora_linear.lora_up.parameters())
    return lora_params


@dataclass
class TTTConfig:
    lr: float = 4e-4
    ags: int = 4
    steps: int = 10
    batch_size: int = 4
    mask_ratio: float = 0.15
    crop_size: int = 1024
    bert_leave_prob: float = 0.1
    bert_replace_prob: float = 0.1
    optimizer: str = "sgd"
    momentum: float = 0.0
    weight_decay: float = 0.0
    seed: Optional[int] = 0
    initial_state_reset: bool = True
    freeze_embeddings: bool = True
    lora_rank: int = 8
    lora_alpha: float = 32.0
    lora_target_class: str = "EsmSelfAttention"

    def verify(self) -> None:
        assert self.lr > 0.0, "TTT learning rate must be positive."
        assert self.ags > 0, "TTT ags must be positive."
        assert self.steps >= 0, "TTT steps must be non-negative."
        assert self.batch_size > 0, "TTT batch_size must be positive."
        assert 0.0 < self.mask_ratio <= 1.0, "TTT mask_ratio must be in (0, 1]."
        assert self.crop_size > 0, "TTT crop_size must be positive."
        assert 0.0 <= self.bert_leave_prob <= 1.0
        assert 0.0 <= self.bert_replace_prob <= 1.0
        assert self.bert_leave_prob + self.bert_replace_prob <= 1.0
        assert self.optimizer in {"sgd", "adamw"}
        assert self.lora_rank >= 0
        assert self.lora_alpha > 0.0


def preserve_model_state(func: Callable[..., Any]) -> Callable[..., Any]:
    @wraps(func)
    def wrapper(self: Any, *args: Any, **kwargs: Any) -> Any:
        was_training = self.training
        original_device = next(self.parameters()).device
        original_requires_grad = {
            name: parameter.requires_grad
            for name, parameter in self.named_parameters()
        }
        try:
            return func(self, *args, **kwargs)
        finally:
            self.train(was_training)
            self.to(original_device)
            for name, parameter in self.named_parameters():
                if name in original_requires_grad:
                    parameter.requires_grad = original_requires_grad[name]
                else:
                    parameter.requires_grad = False
    return wrapper


# =============================================================================
# FastEsmFoldConfig
# =============================================================================

class FastEsmFoldConfig(EsmConfig):
    model_type = "fast_esmfold"

    def __init__(self, attn_backend: str = "sdpa", ttt_config: Optional[Dict[str, Any]] = None, **kwargs):
        super().__init__(**kwargs)
        self.attn_backend = attn_backend
        self.ttt_config = ttt_config or {
            "lr": 4e-4,
            "steps": 10,
            "lora_rank": 8,
            "lora_alpha": 32.0,
        }


# =============================================================================
# FastEsmForProteinFolding
# =============================================================================

class FastEsmForProteinFolding(EsmForProteinFolding):
    """ESMFold with FastESM2 attention backends + built-in Test-Time Training.

    Inherits all folding logic (trunk, structure module, output_to_pdb, infer)
    from transformers.EsmForProteinFolding. Replaces the ESM2 backbone with
    FastESM2 for optimized attention and adds TTT for improved structure prediction.

    Key API:
        result = model.fold_protein("MKTL...", ttt=True)
        # result = {"plddt": float, "ptm": float, "pdb_string": str}
    """
    config_class = FastEsmFoldConfig

    def __init__(self, config: FastEsmFoldConfig):
        super().__init__(config)

        # Replace standard ESM2 backbone with FastESM2 (multi-backend attention)
        # unless use_standard_backbone is set (for TTT debugging/compatibility)
        if not config.ttt_config.get("use_standard_backbone", False):
            self.esm = FastEsmBackbone(config)
            self.esm.requires_grad_(False)
            if config.esmfold_config.fp16_esm:
                self.esm.half()

        # MLM head for TTT (pretrained EsmLMHead: Dense -> GELU -> LN -> Linear)
        self.mlm_head = EsmLMHead(config)

        # TTT state (lazy initialization)
        ttt_kwargs = {k: v for k, v in config.ttt_config.items() if k != "use_standard_backbone"}
        self._ttt_cfg = TTTConfig(**ttt_kwargs)
        self._ttt_cfg.verify()
        self._ttt_initialized = False
        self._ttt_initial_state = None
        self._ttt_generator = torch.Generator()
        if self._ttt_cfg.seed is not None:
            self._ttt_generator.manual_seed(self._ttt_cfg.seed)
        self._non_special_tokens_cache = None
        self._ttt_tokenizer = None

    def _get_ttt_tokenizer(self) -> EsmTokenizer:
        if self._ttt_tokenizer is None:
            self._ttt_tokenizer = EsmTokenizer.from_pretrained("facebook/esm2_t6_8M_UR50D")
        return self._ttt_tokenizer

    def _ensure_ttt_ready(self) -> None:
        """Lazy TTT initialization. Injects LoRA adapters and saves initial state.
        Must be called after weights are loaded (not in __init__)."""
        if self._ttt_initialized:
            return
        self._ttt_initialized = True

        tokenizer = self._get_ttt_tokenizer()
        vocab = tokenizer.get_vocab()
        self._non_special_tokens_cache = [vocab[c] for c in _ESM_STANDARD_AA if c in vocab]

        if self._ttt_cfg.lora_rank > 0:
            self.mlm_head.eval()
            for p in self.mlm_head.parameters():
                p.requires_grad = False
            # Seed global state before LoRA init for reproducible weight initialization
            if self._ttt_cfg.seed is not None:
                torch.manual_seed(self._ttt_cfg.seed)
            self._inject_lora()
        else:
            # Legacy path: jointly-trained random linear projection head
            H = self.config.hidden_size
            V = self.config.vocab_size
            device = next(self.esm.parameters()).device
            self._ttt_lm_proj = nn.Linear(H, V, bias=True).to(device)

        if self._ttt_cfg.initial_state_reset:
            self._ttt_initial_state = self._ttt_get_state()

    @property
    def _uses_lora(self) -> bool:
        return self._ttt_cfg.lora_rank > 0

    def _inject_lora(self) -> None:
        """Inject LoRA adapters into ESM2 attention layers (matching lora_diffusion behavior)."""
        self._lora_params = inject_trainable_lora(
            self.esm,
            target_class_name=self._ttt_cfg.lora_target_class,
            r=self._ttt_cfg.lora_rank,
            scale=self._ttt_cfg.lora_alpha,
        )
        assert len(self._lora_params) > 0, (
            f"No LoRA params injected. Check target_class_name='{self._ttt_cfg.lora_target_class}' "
            f"matches attention modules in the backbone."
        )

    # ---- TTT State Management ----

    def _get_lora_modules(self) -> List[LoraInjectedLinear]:
        """Find all LoraInjectedLinear modules in the backbone."""
        return [m for m in self.esm.modules() if isinstance(m, LoraInjectedLinear)]

    def _ttt_get_state(self) -> Dict[str, Any]:
        if self._uses_lora:
            lora_state = []
            for m in self._get_lora_modules():
                lora_state.append({
                    "down": m.lora_down.weight.data.clone(),
                    "up": m.lora_up.weight.data.clone(),
                })
            return {"_lora_state": lora_state}
        return {
            "esm": copy.deepcopy(self.esm),
            "_ttt_lm_proj": copy.deepcopy(self._ttt_lm_proj),
        }

    def _ttt_set_state(self, state: Dict[str, Any]) -> None:
        if "_lora_state" in state:
            modules = self._get_lora_modules()
            assert len(modules) == len(state["_lora_state"])
            for m, saved in zip(modules, state["_lora_state"]):
                m.lora_down.weight.data.copy_(saved["down"])
                m.lora_up.weight.data.copy_(saved["up"])
            return
        if "esm" in state:
            self.esm = copy.deepcopy(state["esm"])
        if "_ttt_lm_proj" in state:
            self._ttt_lm_proj = copy.deepcopy(state["_ttt_lm_proj"])

    def ttt_reset(self) -> None:
        """Reset model to pre-TTT state (restore initial LoRA or backbone weights)."""
        assert self._ttt_initial_state is not None, "TTT reset requires initial_state_reset=True."
        self._ttt_set_state(self._ttt_initial_state)

    # ---- TTT Core ----

    def _ttt_tokenize(self, seq: str) -> torch.Tensor:
        tokenizer = self._get_ttt_tokenizer()
        out = tokenizer(
            seq,
            return_tensors="pt",
            add_special_tokens=self._uses_lora,
            padding=False,
            truncation=False,
        )
        return out["input_ids"]

    def _ttt_mask_token(self) -> int:
        return self._get_ttt_tokenizer().mask_token_id

    def _ttt_get_non_special_tokens(self) -> List[int]:
        if self._non_special_tokens_cache is not None:
            return self._non_special_tokens_cache
        tokenizer = self._get_ttt_tokenizer()
        vocab = tokenizer.get_vocab()
        self._non_special_tokens_cache = [vocab[c] for c in _ESM_STANDARD_AA if c in vocab]
        return self._non_special_tokens_cache

    def _ttt_predict_logits(self, batch: torch.Tensor) -> torch.Tensor:
        """Run ESM2 backbone + LM head to get MLM logits."""
        # Temporarily unfreeze backbone for gradient flow during TTT
        output = self.esm(input_ids=batch)
        hidden = output.last_hidden_state
        if self._uses_lora:
            return self.mlm_head(hidden)
        return self._ttt_lm_proj(hidden)

    def _ttt_sample_batch(
        self,
        x: torch.Tensor,
    ) -> Tuple[torch.Tensor, torch.Tensor, torch.Tensor, torch.Tensor]:
        _, seq_len = x.shape
        batch_size = self._ttt_cfg.batch_size
        crop_size = min(self._ttt_cfg.crop_size, seq_len)

        x_expanded = x.expand(batch_size, -1)
        if seq_len == crop_size:
            start_indices = torch.zeros(batch_size, dtype=torch.long)
        else:
            start_indices = torch.randint(
                0, seq_len - crop_size + 1, (batch_size,),
                generator=self._ttt_generator,
            ).to(torch.long)

        batch_cropped = torch.stack([
            x_expanded[index, start : start + crop_size]
            for index, start in enumerate(start_indices)
        ])

        non_special_tokens = set(self._ttt_get_non_special_tokens())
        mask = torch.zeros((batch_size, crop_size), dtype=torch.bool)
        mask_token_id = self._ttt_mask_token()

        for row_index in range(batch_size):
            non_special_positions = [
                col for col in range(crop_size)
                if batch_cropped[row_index, col].item() in non_special_tokens
            ]
            assert len(non_special_positions) > 0, "Sequence must contain at least one non-special token."
            num_to_mask = max(1, int(round(len(non_special_positions) * self._ttt_cfg.mask_ratio)))
            sampled_indices = torch.randperm(
                len(non_special_positions), generator=self._ttt_generator,
            )[:num_to_mask]
            positions_to_mask = torch.tensor(non_special_positions, dtype=torch.long)[sampled_indices]
            mask[row_index, positions_to_mask] = True

        batch_masked = batch_cropped.clone()
        for row_index in range(batch_size):
            masked_positions = torch.nonzero(mask[row_index], as_tuple=True)[0]
            for masked_position in masked_positions:
                probability = float(torch.rand(1, generator=self._ttt_generator).item())
                if probability < 1.0 - self._ttt_cfg.bert_leave_prob - self._ttt_cfg.bert_replace_prob:
                    batch_masked[row_index, masked_position] = mask_token_id
                    continue
                if probability < 1.0 - self._ttt_cfg.bert_leave_prob:
                    replacement_candidates = self._ttt_get_non_special_tokens()
                    replacement_index = int(torch.randint(
                        0, len(replacement_candidates), (1,), generator=self._ttt_generator,
                    ).item())
                    batch_masked[row_index, masked_position] = replacement_candidates[replacement_index]

        return batch_masked, batch_cropped, mask, start_indices

    def _ttt_cross_entropy_loss(
        self,
        logits: torch.Tensor,
        targets: torch.Tensor,
        mask: torch.Tensor,
    ) -> torch.Tensor:
        assert logits.ndim == 3, "Logits must be [batch, seq, vocab]."
        _, _, vocab_size = logits.shape
        logits_flat = logits.reshape(-1, vocab_size)
        targets_flat = targets.reshape(-1)
        mask_flat = mask.reshape(-1)
        assert int(mask_flat.sum().item()) > 0, "TTT mask must select at least one token."
        loss = F.cross_entropy(
            logits_flat[mask_flat],
            targets_flat[mask_flat],
            reduction="none",
        )
        masked_tokens_per_seq = mask.sum(dim=1).tolist()
        per_sequence_losses = torch.split(loss, masked_tokens_per_seq)
        return torch.stack([sl.mean() for sl in per_sequence_losses]).mean()

    def _ttt_get_optimizer(self, parameters) -> torch.optim.Optimizer:
        if self._ttt_cfg.optimizer == "sgd":
            return torch.optim.SGD(
                parameters,
                lr=self._ttt_cfg.lr,
                momentum=self._ttt_cfg.momentum,
                weight_decay=self._ttt_cfg.weight_decay,
            )
        return torch.optim.AdamW(
            parameters,
            lr=self._ttt_cfg.lr,
            weight_decay=self._ttt_cfg.weight_decay,
        )

    def _lora_ttt(self, seq: str) -> Dict[str, List[float]]:
        """LoRA TTT: only LoRA adapter weights are trained, mlm_head is frozen."""
        x = self._ttt_tokenize(seq)
        device = next(self.parameters()).device
        non_blocking = device.type == "cuda"
        losses = []

        if self._ttt_cfg.steps == 0:
            return {"losses": losses}

        for parameter in self.parameters():
            parameter.requires_grad = False
        for p in self._lora_params:
            p.requires_grad = True
        optimizer = self._ttt_get_optimizer(self._lora_params)
        optimizer.zero_grad(set_to_none=True)

        self.eval()
        for step in range(self._ttt_cfg.steps * self._ttt_cfg.ags):
            batch_masked, targets, mask, start_indices = self._ttt_sample_batch(x)
            batch_masked = batch_masked.to(device, non_blocking=non_blocking)
            targets = targets.to(device, non_blocking=non_blocking)
            mask = mask.to(device, non_blocking=non_blocking)

            self.train()
            logits = self._ttt_predict_logits(batch_masked)
            loss = self._ttt_cross_entropy_loss(logits, targets, mask)
            loss.backward()
            losses.append(float(loss.detach().cpu().item()))

            if (step + 1) % self._ttt_cfg.ags == 0:
                optimizer.step()
                optimizer.zero_grad(set_to_none=True)

        self.eval()
        return {"losses": losses}

    def _legacy_ttt(self, seq: str) -> Dict[str, List[float]]:
        """Legacy TTT: full fine-tuning of ESM2 backbone with random linear projection head."""
        x = self._ttt_tokenize(seq)
        device = next(self.parameters()).device
        non_blocking = device.type == "cuda"
        losses = []

        if self._ttt_cfg.steps == 0:
            return {"losses": losses}

        # Full fine-tune: all backbone params trainable
        for parameter in self.parameters():
            parameter.requires_grad = False
        for parameter in self.esm.parameters():
            parameter.requires_grad = True
        if self._ttt_cfg.freeze_embeddings:
            for parameter in self.esm.embeddings.parameters():
                parameter.requires_grad = False
        for parameter in self._ttt_lm_proj.parameters():
            parameter.requires_grad = True

        trainable_params = filter(lambda p: p.requires_grad, self.parameters())
        optimizer = self._ttt_get_optimizer(trainable_params)
        optimizer.zero_grad(set_to_none=True)

        self.eval()
        for step in range(self._ttt_cfg.steps * self._ttt_cfg.ags):
            batch_masked, targets, mask, start_indices = self._ttt_sample_batch(x)
            batch_masked = batch_masked.to(device, non_blocking=non_blocking)
            targets = targets.to(device, non_blocking=non_blocking)
            mask = mask.to(device, non_blocking=non_blocking)

            self.train()
            logits = self._ttt_predict_logits(batch_masked)
            loss = self._ttt_cross_entropy_loss(logits, targets, mask)
            loss.backward()
            losses.append(float(loss.detach().cpu().item()))

            if (step + 1) % self._ttt_cfg.ags == 0:
                optimizer.step()
                optimizer.zero_grad(set_to_none=True)

        self.eval()
        return {"losses": losses}

    @preserve_model_state
    def ttt(self, seq: str) -> Dict[str, List[float]]:
        """Run test-time training on a single sequence using masked language modeling.

        Adapts the ESM2 backbone (via LoRA or full fine-tuning) to the input sequence
        before structure prediction. Call fold_protein(seq, ttt=True) for the full pipeline.

        Args:
            seq: Protein sequence (single-letter amino acid codes)

        Returns:
            Dict with "losses" key containing per-step MLM loss values
        """
        self._ensure_ttt_ready()
        # TTT requires fp32 for stable gradient computation. ESMFold typically
        # runs the backbone in fp16, but small LoRA updates vanish in half precision.
        esm_dtype = next(self.esm.parameters()).dtype
        if esm_dtype != torch.float32:
            self.esm.float()
            self.mlm_head.float()
        if self._uses_lora:
            result = self._lora_ttt(seq)
        else:
            result = self._legacy_ttt(seq)
        # Restore original dtype (backbone back to fp16 for inference)
        if esm_dtype != torch.float32:
            self.esm.to(esm_dtype)
            self.mlm_head.to(esm_dtype)
        return result

    # ---- High-Level API ----

    def _fold_single(self, sequence: str, return_pdb_string: bool = True) -> Dict[str, Any]:
        """Fold a sequence once and return pLDDT, ptm, and optionally PDB string."""
        with torch.no_grad():
            output = self.infer(sequence)
        plddt = output["plddt"]
        # plddt shape is (batch, L, 37) - per-atom across atom37 types.
        # Use CA atom (index 1) only, matching PDB B-factor output.
        if plddt.dim() == 3:
            mean_plddt = float(plddt[:, :, 1].mean().item())
        elif plddt.dim() == 2:
            mean_plddt = float(plddt[:, 1].mean().item())
        else:
            mean_plddt = float(plddt.mean().item())
        result = {
            "plddt": mean_plddt,
            "ptm": float(output["ptm"].item()) if "ptm" in output else None,
        }
        if return_pdb_string:
            pdb_strings = self.output_to_pdb(output)
            result["pdb_string"] = pdb_strings[0] if isinstance(pdb_strings, list) else pdb_strings
        return result

    def fold_protein(
        self,
        sequence: str,
        return_pdb_string: bool = True,
    ) -> Dict[str, Any]:
        """Fold a protein sequence with test-time training.

        Runs TTT (masked language model adaptation via LoRA) for the configured
        number of steps, folding after each optimizer step to track pLDDT. Returns
        the structure with the highest pLDDT across all steps (including baseline).

        Args:
            sequence: Protein sequence (single-letter amino acid codes)
            return_pdb_string: If True, include PDB string in output

        Returns:
            Dict with keys:
                - plddt: float, best mean pLDDT across all TTT steps
                - ptm: float, predicted TM-score from best step
                - pdb_string: str (if return_pdb_string=True), PDB from best step
                - step_plddts: list[float], pLDDT at each step [baseline, s1, ..., s10]
                - best_step: int, which step produced best structure (0=baseline)
        """
        self._ensure_ttt_ready()

        # Cast to fp32 for TTT stability
        esm_dtype = next(self.esm.parameters()).dtype
        if esm_dtype != torch.float32:
            self.esm.float()
            self.mlm_head.float()

        device = next(self.parameters()).device
        non_blocking = device.type == "cuda"

        # Step 0: baseline fold (no TTT adaptation)
        best = self._fold_single(sequence, return_pdb_string=return_pdb_string)
        step_plddts = [best["plddt"]]

        if self._ttt_cfg.steps > 0:
            # Tokenize for masked LM training
            x = self._ttt_tokenize(sequence)

            # Freeze all, unfreeze LoRA
            for p in self.parameters():
                p.requires_grad = False
            if self._uses_lora:
                for p in self._lora_params:
                    p.requires_grad = True
                optimizer = self._ttt_get_optimizer(self._lora_params)
            else:
                for p in self.esm.parameters():
                    p.requires_grad = True
                if self._ttt_cfg.freeze_embeddings:
                    for p in self.esm.embeddings.parameters():
                        p.requires_grad = False
                for p in self._ttt_lm_proj.parameters():
                    p.requires_grad = True
                trainable = [p for p in self.parameters() if p.requires_grad]
                optimizer = self._ttt_get_optimizer(trainable)
            optimizer.zero_grad(set_to_none=True)

            self.eval()
            for step in range(self._ttt_cfg.steps * self._ttt_cfg.ags):
                batch_masked, targets, mask, _start = self._ttt_sample_batch(x)
                batch_masked = batch_masked.to(device, non_blocking=non_blocking)
                targets = targets.to(device, non_blocking=non_blocking)
                mask = mask.to(device, non_blocking=non_blocking)

                self.train()
                logits = self._ttt_predict_logits(batch_masked)
                loss = self._ttt_cross_entropy_loss(logits, targets, mask)
                loss.backward()

                if (step + 1) % self._ttt_cfg.ags == 0:
                    optimizer.step()
                    optimizer.zero_grad(set_to_none=True)

                    # Fold after this optimizer step
                    self.eval()
                    current = self._fold_single(sequence, return_pdb_string=return_pdb_string)
                    step_plddts.append(current["plddt"])
                    if current["plddt"] > best["plddt"]:
                        best = current

            self.eval()

            # Restore requires_grad
            for p in self.parameters():
                p.requires_grad = False

        # Reset LoRA weights for next sequence
        self.ttt_reset()

        # Restore dtype
        if esm_dtype != torch.float32:
            self.esm.to(esm_dtype)
            self.mlm_head.to(esm_dtype)

        return {
            "plddt": best["plddt"],
            "ptm": best["ptm"],
            "pdb_string": best.get("pdb_string"),
            "step_plddts": step_plddts,
            "best_step": step_plddts.index(max(step_plddts)),
        }