design.py

"""Closed-form inverse design against the classifier's linear heads.

Because each head is linear in 8-mer counts, sequences that maximize or minimize a
head score can be found by coordinate ascent. Two modes:
  - free: design a sequence from scratch toward maximum or minimum score
  - synonymous: re-choose codons of a given coding sequence to push the score while
    preserving the encoded protein

Usage:
    from design import free_design, synonymous_design
    from model import DnaOriginClassifier
    clf = DnaOriginClassifier("model.safetensors")
    seq = free_design(clf, length=300, direction="max")        # maximally host-like
    recoded = synonymous_design(clf, cds, direction="min")     # least host-like, same protein
"""
import random
import itertools

BASES = "ACGT"
_CODON = {}
_aa = "KNKNTTTTRSRSIIMIQHQHPPPPRRRRLLLLEDEDAAAAGGGGVVVV*Y*YSSSSLFLF*CWCLFLF"  # standard code, see below
# build the standard genetic code explicitly to avoid ordering ambiguity
_BASES4 = "TCAG"
_AAS = ("FFLLSSSSYY**CC*WLLLLPPPPHHQQRRRRIIIMTTTTNNKKSSRRVVVVAAAADDEEGGGG")
_i = 0
for a in _BASES4:
    for b in _BASES4:
        for c in _BASES4:
            _CODON[a + b + c] = _AAS[_i]; _i += 1
_AA2COD = {}
for cod, aa in _CODON.items():
    _AA2COD.setdefault(aa, []).append(cod)


def _protein(seq):
    return "".join(_CODON.get(seq[i:i + 3], "X") for i in range(0, len(seq) - 2, 3))


def free_design(clf, length=300, direction="max", passes=6, seed=0):
    rng = random.Random(seed)
    seq = [rng.choice(BASES) for _ in range(length)]
    d = 1 if direction == "max" else -1
    for _ in range(passes):
        for p in range(length):
            best, bs = seq[p], clf.host_score("".join(seq))
            for nb in BASES:
                seq[p] = nb
                sc = clf.host_score("".join(seq))
                if d * sc > d * bs:
                    bs, best = sc, nb
            seq[p] = best
    return "".join(seq)


def synonymous_design(clf, cds, direction="max", passes=4):
    cod = [cds[i:i + 3] for i in range(0, len(cds) - 2, 3)]
    d = 1 if direction == "max" else -1
    for _ in range(passes):
        for ci in range(len(cod)):
            aa = _CODON.get(cod[ci])
            if aa not in _AA2COD:
                continue
            best, bs = cod[ci], clf.host_score("".join(cod))
            for cand in _AA2COD[aa]:
                cod[ci] = cand
                sc = clf.host_score("".join(cod))
                if d * sc > d * bs:
                    bs, best = sc, cand
            cod[ci] = best
    out = "".join(cod)
    assert _protein(out) == _protein(cds), "protein not preserved"
    return out


if __name__ == "__main__":
    from model import DnaOriginClassifier
    clf = DnaOriginClassifier()
    mx = free_design(clf, 300, "max")
    mn = free_design(clf, 300, "min")
    print("max-host design score:", round(clf.host_score(mx), 2))
    print("min-host design score:", round(clf.host_score(mn), 2))