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Understanding the interplay among processes that occur over different timescales is a challenging issue in the physics of systems regulation. In gene regulation, the timescales for changes in chromatin states can differ from those for changes in the concentration of product protein, raising questions about how to unde...
Due to the increasing use of nanometric cerium oxide in applications, concerns about the toxicity of these particles have been raised and have resulted in a large number of investigations. We report here on the interactions between 7 nm anionically charged cerium oxide particles and living mammalian cells.
Cell experiments with large, short electric field pulses of opposite polarity reveal a remarkable phenomenon: Bipolar cancellation (BPC). Typical defining experiments involve quantitative observation of tracer molecule influx at times of order 100 s post pulsing.
Kinesin superfamily protein UNC-104, a member of the kinesin-3 family, transports synaptic vesicle precursors (SVPs). In this study, the number of active UNC-104 molecules hauling a single SVP in axons in the worm Caenorhabditis elegans was counted by applying a newly developed non-invasive force measurement technique...
Microbial communities feature an immense diversity of species and this diversity is linked with outcomes ranging from ecosystem stability to medical prognoses. Yet the mechanisms underlying microbial diversity are under debate.
Brain injuries resulting from mechanical trauma represent an ongoing global public health issue. Several $\textit{in vitro}$ and $\textit{in vivo}$ models for traumatic brain injury (TBI) continue to be developed for delineating the various complex pathophysiological processes involved in its onset and progression.
Many studies have revealed that confined water chain flipping is closely related to the spatial size and even quantum effects of the confinement environment. Here, we show that these are not the only factors that affect the flipping process of a confined water chain.
Unlike other tissue types, like epithelial tissue, which consist of cells with a much more homogeneous structure and function, the nervous tissue spans in a complex multilayer environment whose topographical features display a large spectrum of morphologies and size scales. Traditional cell cultures, which are based o...
Bacterial chemotaxis is controlled by the conformational changes of the receptors, in response to the change of the ambient chemical concentration. In a statistical mechanical approach, the signalling due to the conformational changes is a thermodynamic average quantity, dependent on the temperature and the total ener...
Using a simple hydrophobic/polar protein model, we perform a Monte Carlo study of the thermodynamics and kinetics of binding to a target structure for two closely related sequences, one of which has a unique folded state while the other is unstructured. We obtain significant differences in their binding behavior.
Converting peptide sequences into useful representations for downstream analysis is a common step in computational modeling and cheminformatics. Furthermore, peptide drugs (e.g., Semaglutide, Degarelix) often take advantage of the diverse chemistries found in noncanonical amino acids (NCAAs), altered stereochemistry, ...
Protein aggregates in the brain play a central role in cognitive decline and structural damage associated with neurodegenerative diseases. For instance, in Alzheimer's disease the formation of Amyloid-beta plaques and tau proteins neurofibrillary tangles follows from the accumulation of different proteins into lar...
Analyzing nonlinear conformational relaxation dynamics in elastic networks corresponding to two classical motor proteins, we find that they respond by well-defined internal mechanical motions to various initial deformations and that these motions are robust against external perturbations. We show that this behavior is...
The protein NLRP3 and its complexes are associated with an array of inflammatory pathologies, among which neurodegenerative, autoimmune, and metabolic diseases. Targeting the NLRP3 inflammasome represents a promising strategy for easing the symptoms of pathologic neuroinflammation.
Experiments show that for many two state folders the free energy of the native state DG_ND([C]) changes linearly as the denaturant concentration [C] is varied. The slope, m = d DG_ND([C])/d[C], is nearly constant.
Deciphering the links between amino acid sequence and amyloid fibril formation is key for understanding protein misfolding diseases. Here we use Monte Carlo simulations to study aggregation of short peptides in a coarse-grained model with hydrophobic-polar (HP) amino acid sequences and correlated side chain orientatio...
Numerous cellular functions rely on protein$\unicode{x2013}$protein interactions. Efforts to comprehensively characterize them remain challenged however by the diversity of molecular recognition mechanisms employed within the proteome.
We have studied the mobility of the folding catalyst, protein disulphide-isomerase (PDI), by molecular dynamics and by a rapid approach based on flexibility. We analysed our simulations using measures of backbone movement, relative positions and orientations of domains, and distances between functional sites.
Repeat proteins are made with tandem copies of similar amino acid stretches that fold into elongated architectures. Due to their symmetry, these proteins constitute excellent model systems to investigate how evolution relates to structure, folding and function.
Electrical signaling via voltage-gated ion channels depends upon the function of the voltage sensor (VS), identified with the S1-S4 domain of voltage-gated K channels. Here we investigate some physical aspects of the sliding-helix model of the VS using simulations based on VS charges, linear dielectrics and whole-body...
Melanoma is one of the most dangerous skin malignancies due to its high metastatic tendency and high mortality. Activation of key signaling pathways enforcing melanoma progression depends on phosphorylation of tyrosine kinases, and oxidative stress.
Amyloid fibers are aggregates of proteins. They are built out of a peptide called $\beta$--amyloid (A$\beta$) containing between 41 and 43 residues, produced by the action of an enzyme which cleaves a much larger protein known as the Amyloid Precursor Protein (APP).
Being capable of characterizing DNA local bending is essential to understand thoroughly many biological processes because they involve a local bending of the double helix axis, either intrinsic to the sequence or induced by the binding of proteins. Developing a method to measure DNA bend angles that does not perturb t...
Hyperbaric oxygen therapy (HBOT) proves vital in saving lives by elevating the partial pressure of oxygen (pO2). However, HBOT may also have toxic effects, including lung and retinal damage (peripheral HBOT toxicity), muscle spasms and violent myoclonic convulsions (CNS HBOT toxicity), which may even lead to death if ...
A simple theory of ion permeation through a channel is presented, in which diffusion occurs according to Fick's law and drift according to Ohm's law, in the electric field determined by all the charges present. This theory accounts for permeation in the channels studied to date in a wide range of solutions.
Machine learning is often used in virtual screening to find compounds that are pharmacologically active on a target protein. The weave module is a type of graph convolutional deep neural network that uses not only features focusing on atoms alone (atom features) but also features focusing on atom pairs (pair features)...
DNA and proteins are chiral: their three-dimensional structure cannot be superimposed with its mirror image. Circular dichroism spectroscopy is widely used to characterize chiral compounds, but data interpretation is difficult in the case of mixtures.
A stochastic model for the dynamics of enzymatic catalysis in explicit, effective solvents under physiological conditions is presented. Analytically-computed first passage time densities of a diffusing particle in a spherical shell with absorbing boundaries are combined with densities obtained from explicit simulation...
The growing significance of RNA engineering in diverse biological applications has spurred interest in developing AI methods for structure-based RNA design. While diffusion models have excelled in protein design, adapting them for RNA presents new challenges due to RNA's conformational flexibility and the computat...
The epidermis is a specialized epithelium that constitutes the outermost layer of the skin, and it provides a protective barrier against environmental assaults. Primarily consisting of multilayered keratinocytes, the epidermis is continuously renewed by proliferation of stem cells and the differentiation of their prog...
The kinetic folding of RNA sequences into secondary structures is modeled as a complex adaptive system, the components of which are possible RNA structural rearrangements (SRs) and their associated bases and base pairs. RNA bases and base pairs engage in local stacking interactions that determine the probabilities (or...
Engineering molecules to exhibit precise 3D intermolecular interactions with their environment forms the basis of chemical design. In ligand-based drug design, bioisosteric analogues of known bioactive hits are often identified by virtually screening chemical libraries with shape, electrostatic, and pharmacophore simi...
Mutations and oxidative modification in the protein Cu,Zn superoxide dismutase (SOD1) have been implicated in the death of motor neurons in amyotrophic lateral sclerosis (ALS), a presently incurable, invariably fatal neurodegenerative disease. Here we employ steered, all-atom molecular dynamics simulations in implicit...
Abnormal hemoglobins can have major consequences for tissue delivery of oxygen. Correct diagnosis of hemoglobinopathies with altered oxygen affinity requires a determination of hemoglobin oxygen dissociation curve (ODC), which relates the hemoglobin oxygen saturation to the partial pressure of oxygen in the blood.
Much of the complexity observed in gene regulation originates from cooperative protein-DNA binding. While studies of the target search of proteins for their specific binding sites on the DNA have revealed design principles for the quantitative characteristics of protein-DNA interactions, no such principles are known f...
We present a general framework to study the thermodynamic denaturation of double-stranded DNA under superhelical stress. We report calculations of position- and size-dependent opening probabilities for bubbles along the sequence.
Cholesterol plays an essential role in biological membranes and is crucial for maintaining their stability and functionality. It is necessary for a variety of membranes, including planar bilayers, liposomes, curved bilayers, nanodiscs, and proteoliposomes.
We present a thermodynamically robust coarse-grained model to simulate folding of RNA in monovalent salt solutions. The model includes stacking, hydrogen bond and electrostatic interactions as fundamental components in describing the stability of RNA structures.
Understanding how proteins structurally interact is crucial to modern biology, with applications in drug discovery and protein design. Recent machine learning methods have formulated protein-small molecule docking as a generative problem with significant performance boosts over both traditional and deep learning basel...
Identifying protein functional sites (PFSs) and protein-ligand interactions (PLIs) are critically important in understanding the protein function and the involved biochemical reactions. As large amount of unknown proteins are quickly accumulated in this post-genome era, an urgent task arises to predict PFSs and PLIs a...
Dynorphin is a neuropeptide involved in pain, addiction and mood regulation. It exerts its activity by binding to the kappa opioid receptor (KOP) which belongs to the large family of G-protein coupled receptors.
This paper proposes an iterative algorithm for choosing gradient directions use to reconstruct white matter fibers in the brain. The present study is not focusing on data acquisition where scanning is performed.
In this study we evaluate, at full atomic detail, the folding processes of two small helical proteins, the B domain of protein A and the Villin headpiece. Folding kinetics are studied by performing a large number of ab initio Monte Carlo folding simulations using a single transferable all-atom potential.
Post-translational modifications (PTMs) in proteins occur after the process of translation. PTMs account for many cellular processes such as deoxyribonucleic acid (DNA) repair, cell signaling and cell death.
Knots in proteins have been proposed to resist proteasomal degradation. Ample evidence associates proteasomal degradation with neurodegeneration.
Statistical models for families of evolutionary related proteins have recently gained interest: in particular pairwise Potts models, as those inferred by the Direct-Coupling Analysis, have been able to extract information about the three-dimensional structure of folded proteins, and about the effect of amino-acid subst...
Previous research has shown a strong correlation of protein folding rates to the native state geometry, yet a complete explanation for this dependence is still lacking. Here we study the rate-geometry relationship with a simple statistical physics model, and focus on two classes of model geometries, representing ideal...
Models in systems biology are mathematical descriptions of biological processes that are used to answer questions and gain a better understanding of biological phenomena. Dynamic models represent the network through rates of the production and consumption for the individual species.
Cryo-Electron Microscopy (cryo-EM) has become an extremely powerful method for resolving structural details of large biomolecular complexes. However, challenging problems in single-particle methods remain open because of (1) the low signal-to-noise ratio in EM; and (2) the potential anisotropy and lack of coverage of ...
The DNA double helix is a polyanionic macromolecule that in water solutions is neutralized by metal ions (counterions). The property of the counterions to stabilize the water network (positive hydration) or to make it friable (negative hydration) is important in terms of the physical mechanisms of stabilization of the...
Understanding the connection between complex structural features of RNA and biological function is a fundamental challenge in evolutionary studies and in RNA design. However, building datasets of RNA 3D structures and making appropriate modeling choices remains time-consuming and lacks standardization.
Determining the mechanism by which transfer RNAs (tRNAs) rapidly and precisely transit through the ribosomal A, P and E sites during translation remains a major goal in the study of protein synthesis. Here, we report the real-time dynamics of the L1 stalk, a structural element of the large ribosomal subunit that is im...
Mechanisms of immunity, and of the host-pathogen interactions in general are among the most fundamental problems of medicine, ecology, and evolution studies. Here, we present a microscopic, protein-level, sequence-based model of immune system, with explicitly defined interactions between host and pathogen proteins.
Recently exciting progress has been made on protein contact prediction, but the predicted contacts for proteins without many sequence homologs is still of low quality and not very useful for de novo structure prediction. This paper presents a new deep learning method that predicts contacts by integrating both evolutio...
Robust and efficient interpretation of QSAR methods is quite useful to validate AI prediction rationales with subjective opinion (chemist or biologist expertise), understand sophisticated chemical or biological process mechanisms, and provide heuristic ideas for structure optimization in pharmaceutical industry. For t...
We extend recent methods for parametric sequence alignment to the parameter space for scoring RNA folds. This involves the construction of an RNA polytope.
Selected ribonucleotide sequences bind well to zwitterionic phospholipid bilayer membranes, though randomized RNAs do not. There are no evident repeated sequences in selected membrane binding RNAs.
Relative lifetimes of inherent double stranded DNA openings with lengths up to ten base pairs are presented for different gene promoters and corresponding mutants that either increase or decrease transcriptional activity, in the framework of the Peyrard-Bishop-Dauxois model. Extensive microcanonical simulations are us...
The coding space of protein sequences is shaped by evolutionary constraints set by requirements of function and stability. We show that the coding space of a given protein family--the total number of sequences in that family--can be estimated using models of maximum entropy trained on multiple sequence alignments of n...
Finite size effects on the cooperative thermal denaturation of proteins are considered. A dimensionless measure of cooperativity, Omega, scales as N^zeta, where N is the number of amino acids.
A tandem cell is proposed for DNA sequencing in which an exonuclease enzyme cleaves bases (mononucleotides) from a strand of DNA for identification inside a nanopore. It has two nanopores and three compartments with the structure [cis1, upstream nanopore (UNP), trans1=cis2, downstream nanopore (DNP), trans2].
Protein language models leverage evolutionary information to perform state-of-the-art 3D structure and zero-shot variant prediction. Yet, extracting and explaining all the mutational interactions that govern model predictions remains difficult as it requires querying the entire amino acid space for $n$ sites using $20...
We show that the hydrophobicity of sequences is the leading term in Miyazawa-Jernigan interactions. Being the source of additive (solvation) terms in pair-contact interactions, they were used to reduce the energy parameters while resulting in a clear vector manipulation of energy.
In this paper a quantum mechanical description of the assembly/disassembly process for microtubules is proposed. We introduce creation and annihilation operators that raise or lower the microtubule length by a tubulin layer.
We introduce a topology-based nonlinear network model of protein dynamics with the aim of investigating the interplay of spatial disorder and nonlinearity. We show that spontaneous localization of energy occurs generically and is a site-dependent process.
Despite nearly two scores of research on RNA secondary structure and RNA-RNA interaction prediction, the accuracy of the state-of-the-art algorithms are still far from satisfactory. Researchers have proposed increasingly complex energy models and improved parameter estimation methods in anticipation of endowing their ...
Two-dimensional semiflexible polymer rings are studied both by imaging circular DNA adsorbed on a mica surface and by Monte Carlo simulations of phantom polymers as well as of polymers with finite thickness. Comparison of size and shape of the different models over the full range of flexibilities shows that excluded v...
In the cell, proteins fold and perform complex functions through global structural rearrangements. Function requires a protein to be at the brink of stability to be susceptible to small environmental fluctuations, yet stable enough to maintain structural integrity.
Resonance energy transfer methods are in wide use for evaluating protein-protein interactions and protein conformational changes in living cells. Fluorescence resonance energy transfer (FRET) measures energy transfer as a function of the acceptor:donor ratio, generating FRET saturation curves.
We introduce a new measure of antigenic distance between influenza A vaccine and circulating strains. The measure correlates well with efficacies of the H3N2 influenza A component of the annual vaccine between 1971 and 2004, as do results of a theory of the immune response to influenza following vaccination.
Introduction: Gap junctions play an important role in the cell proliferation in mammalian cells as well as carcinogenesis. However, there are controversial issues about their role in cancer pathogenesis.
Determining the folding core of a protein yields information about its folding process and dynamics. The experimental procedures for identifying the amino acids which make up the folding core include hydrogen-deuterium exchange and $\Phi$-value analysis and can be expensive and time consuming.
Damaged or mismatched bases in DNA can be repaired by Base Excision Repair (BER) enzymes that replace the defective base. Although the detailed molecular structures of many BER enzymes are known, how they colocalize to lesions remains unclear.
Logarithmic oscillations superimposed on a power-law trend appear in the behavior of various complex hierarchical systems. In this paper, we study the logarithmic oscillations of relaxation curves in p-adic diffusion models that are used to describe the conformational dynamics of protein.
Biocatalysis is a promising approach to sustainably synthesize pharmaceuticals, complex natural products, and commodity chemicals at scale. However, the adoption of biocatalysis is limited by our ability to select enzymes that will catalyze their natural chemical transformation on non-natural substrates.
Phytochemicals are plant-derived secondary metabolites, which may exert many biological activities in humans, including anticancer properties. Although recent findings appear to support their role in cancer prevention and treatment, this issue is still controversial.
The importance of understanding the mechanism of protein aggregation into insoluble amyloid fibrils relies not only on its medical consequences, but also on its more basic properties of self--organization. The discovery that a large number of uncorrelated proteins can form, under proper conditions, structurally similar...
The Yakushevich (Y) model provides a very simple pictures of DNA torsion dynamics, yet yields remarkably correct predictions on certain physical characteristics of the dynamics. In the standard Y model, the interaction between bases of a pair is modelled by a harmonic potential, which becomes anharmonic when described...
We review and further develop an analytical model that describes how thermodynamic constraints on the stability of the native state influence protein evolution in a site-specific manner. To this end, we represent both protein sequences and protein structures as vectors: Structures are represented by the principal eige...
Language models for biological and chemical sequences enable crucial applications such as drug discovery, protein engineering, and precision medicine. Currently, these language models are predominantly based on Transformer architectures.
Proteins are a matter of dual nature. As a physical object, a protein molecule is a folded chain of amino acids with multifarious biochemistry.
In this paper we will review various aspects of the biology of prions and focus on what is currently known about the mammalian PrP prion. Also we briefly describe the prions of yeast and other fungi.
In this paper we work out a parameterization of the environment noise within the Haken-Strobl-Reinenker (HSR) model for the PE545 light-harvesting complex based on atomic-level quantum mechanics/molecular mechanics (QM/MM) simulations. We use this approach to investigate the role of different auto- and cross-correlati...
Though the problem of sequence-reversed protein folding is largely unexplored, one might speculate that reversed native protein sequences should be significantly more foldable than purely random heteropolymer sequences. In this article, we investigate how the reverse-sequences of native proteins might fold by examinin...
The high computational cost of carrying out molecular dynamics simulations of even small-size proteins is a major obstacle in the study, at atomic detail and in explicit solvent, of the physical mechanism which is at the basis of the folding of proteins. Making use of a biasing algorithm, based on the principle of the...
We investigate the presence of structural collective motions on a picosecond time scale for the heme protein, cytochrome c, as a function of oxidation and hydration, using terahertz (THz) time-domain spectroscopy and molecular dynamics simulations. The THz response dramatically increases with oxidation, with the large...
In this paper we show the existence of three dimensional rigid, and thus unfoldable, lattice conformations. The structure we found has 450+ bonds, and we provide a computer assisted proof of the existence of such structures.
The Landau-Ginzburg-Wilson paradigm is applied to model the low-temperature crystallographic C$\alpha$ backbone structure of sperm whale myoglobin. The Glauber protocol is employed to simulate its response to an increase in ambient temperature.
Despite the spontaneity of some in vitro protein folding reactions, native folding in vivo often requires the participation of barrel-shaped multimeric complexes known as chaperonins. Although it has long been known that chaperonin substrates fold upon sequestration inside the chaperonin barrel, the precise mechanism ...
The precise details of how myosin-V coordinates the biochemical reactions and mechanical motions of its two head elements to engineer effective processive molecular motion along actin filaments remain unresolved. We compare a quantitative kinetic model of the myosin-V walk, consisting of five basic states augmented by...
The 2024 Nobel Prize in Chemistry was awarded in part for protein structure prediction using AlphaFold2, an artificial intelligence/machine learning (AI/ML) model trained on vast amounts of sequence and 3D structure data. AlphaFold2 and related models, including RoseTTAFold and ESMFold, employ specialized neural netwo...
Both genomic stability and sustenance of day-to-day life rely on efficient and accurate readout of the genetic code. Single-molecule experiments show that transcription and replication are highly stochastic and irregular processes, with the polymerases frequently pausing and even reversing direction.
The effects of purification methods and its hypolipidemic function on the total flavonoids of Aurea Helianthus flower were investigated. Liquid-liquid extraction of ethanol extract from Aurea Helianthus flower was carried out by using different polar solvents.
Lycopene contributes to the red-colored pigmentation of fruits and vegetables, and it is a fat-soluble carotenoid with antioxidant properties. Epidemiological studies have shown the significant health benefits associated to the consumption of lycopene rich foods, because of the anti-cancer properties.
We develop a robust coarse-grained model for single and double stranded DNA by representing each nucleotide by three interaction sites (TIS) located at the centers of mass of sugar, phosphate, and base. The resulting TIS model includes base-stacking, hydrogen bond, and electrostatic interactions as well as bond-stretc...
Recent advances in protein structure prediction have achieved near-atomic accuracy for well-folded proteins. However, current benchmarks inadequately assess model performance in biologically challenging contexts, especially those involving intrinsically disordered regions (IDRs), limiting their utility in applications...
Protein crystal production is a major bottleneck for the structural characterisation of proteins. To advance beyond large-scale screening, rational strategies for protein crystallization are crucial.
Energy evaluation using fast Fourier transforms enables sampling billions of putative complex structures and hence revolutionized rigid protein-protein docking. However, in current methods efficient acceleration is achieved only in either the translational or the rotational subspace.
We present a top-down approach to the study of the dynamics of icosahedral virus capsids, in which each protein is approximated by a point mass. Although this represents a rather crude coarse-graining, we argue that it highlights several generic features of vibrational spectra which have been overlooked so far.
The molecular motor protein kinesin plays a key role in fundamental cellular processes such as intracellular transport, mitotic spindle formation, and cytokinesis, with important implications for neurodegenerative and cancer disease pathways. Recently, kinesin has been studied as a paradigm for the tailored design of ...

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