Biology subjects

Morozova, T. I.

Publications and source records attributed to Morozova, T. I..

5 recordsLinked to original sources

bioRxiv2026

Towards transferable explicit-solvent coarse-grained models for biomolecular condensates

Biomolecular condensates formed by intrinsically disordered proteins require molecular models that accurately describe proteins in both dilute solution and condensed phases. Explicit-solvent coarse-grained models offer an attractive balance between chemical resolution and computational efficiency. Yet, it remains unclear whether improving dilute-state properties is sufficient to obtain an accurate description of condensates. Here, we address this question by introducing minimal modifications to the Martini 3 force field that combine recent advances in bonded interactions with refined protein-water interactions and strengthened glycine self-interactions, while preserving the underlying chemical transferability of the model. The resulting model substantially improves the description of single-chain conformations across a diverse benchmark of disordered proteins. We then investigate phase separation of the well-characterized low-complexity domain of heterogeneous nuclear ribonucleoprotein A1 and its sequence variants. The model reproduces several key physicochemical properties of biomolecular condensates, including chain expansion in the dense phase, sequence-dependent intermolecular contacts, protein diffusion and its relation to single-chain dimensions, and hydration, while revealing quantitative limitations in condensate density, phase equilibria, and ion partitioning. Our results show that improving dilute-state behaviour translates into a better description of condensed-phase properties, including condensate density, but is not sufficient to quantitatively reproduce the equilibrium between the dilute and dense phases.

biophysics↗

bioRxiv2025

Advancing in silico drug design with Bayesian refinement of AlphaFold models

Virtual screening has become an indispensable tool in modern structure-based drug discovery, enabling the identification of candidate molecules by computationally evaluating their potential to bind target proteins. The accuracy of such screenings critically depends on the quality of the target structures employed. Recent advances in protein structure prediction, particularly AlphaFold2, have revolutionized this field with unprecedented accuracy. However, AlphaFold2 models often exhibit limitations in local structural details, especially within binding pockets, which limit their utility for small molecule docking. In contrast, molecular dynamics simulations with accurate atomistic force fields can refine protein structures, but lack the ability to leverage the structural information provided by deep learning approaches. Here, we introduce bAIes, an integrative method that bridges this gap by combining physics-based force fields with data-driven predictions through Bayesian inference. Crucially, bAIes demonstrates a superior ability to discriminate between binders and non-binders in virtual screening campaigns, outperforming both AlphaFold2 and molecular dynamics-refined models. By enhancing the usability of AlphaFold2 models without requiring extensive experimental or computational resources, bAIes offers a convenient solution to a longstanding challenge in structure-based drug design, potentially accelerating the early phases of drug discovery.

bioinformatics↗

bioRxiv2024

Intrinsically disordered proteins can behave as different polymers across their conformational ensemble

Intrinsically disordered proteins (IDPs) are macromolecules, which in contrast to well-folded proteins, explore a large number of conformationally heterogeneous states. In this work, we investigate the conformational space of the disordered protein {beta}-casein using Hamiltonian replica exchange atomistic molecular dynamics simulations in explicit water. The energy landscape contains a global minimum along with two shallow funnels. Employing static polymeric scaling laws separately for individual funnels, we find that they cannot be described by the same polymeric scaling exponent. Around the global minimum, the conformations are globular, whereas in the vicinity of local minima we recover coil-like scaling. To elucidate the implications of structural diversity on equilibrium dynamics, we initiate standard molecular dynamics simulations in the NVT ensemble with representative conformations from each funnel. Global and internal motions for different classes of trajectories show heterogeneous dynamics with globule to coil-like signatures. Thus, IDPs can behave as entirely different polymers in different regions of the conformational space. TOC Graphic O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=111 SRC="FIGDIR/small/615433v2_ufig1.gif" ALT="Figure 1"> View larger version (28K): org.highwire.dtl.DTLVardef@14a0ddorg.highwire.dtl.DTLVardef@4d2af5org.highwire.dtl.DTLVardef@3f4b64org.highwire.dtl.DTLVardef@16ea7e7_HPS_FORMAT_FIGEXP M_FIG C_FIG

biophysics↗

bioRxiv2023

Sequence length controls coil-to-globule transition in elastin-like polypeptides

Phase separation of disordered proteins resulting in the formation of biocondensates has received significant attention due to its fundamental role in cellular organization and functioning and is sought after in many applications. For instance, the liquid-liquid phase separation of tropoelastin initiates the hierarchical assembly process of elastic fibers, which are key components of the extracellular matrix providing resilience and elasticity to biological tissues. Inspired by the hydrophobic domains of tropoelastin, elastin-like polypeptides (ELPs) were derived which exhibit a similar phase behavior. Even though, it appeared almost certain that elastin condensates retain liquid-like properties, a recent experimental study questioned this viewpoint by demonstrating that the aggregate state of elastin-derived materials can depend on the length of hydrophobic domains. Here, we employ state-of-the-art atomistic modeling to resolve the conformational ensembles of a single ELP as a function of its sequence length in the temperature range relevant to possible applications. For the first time, we report the free energy profiles of ELPs in the vicinity of conformational transitions which show more compact polypeptide conformations at higher temperatures in accord with their thermoresponsive nature. We access the conformations visited by ELPs through descriptors from polymer physics. We find that short ELPs always remain in coil-like conformations, while the longer ones prefer globule states. The former engages in intrapeptide hydrogen bonds temporarily retaining their liquid-like properties while the latter forms long-lived (hundreds of nanoseconds) intra-peptide hydrogen bonds attributed to ordered secondary structure motifs such as {beta}-bridges and turns. Our work demonstrates the importance of the sequence length as a modulator of conformational properties at a single chain and possibly explains the change in aggregate state in elastin condensates.

biophysics↗

bioRxiv2022

Structural and Dynamical Properties of Elastin-Like Peptides near their Lower Critical Solution Temperature

Elastin-like peptides (ELPs) are artificially derived intrinsically disordered proteins (IDPs) mimicking the hydrophobic repeat unit in the protein elastin. ELPs are characterized by a lower critical solution temperature (LCST) in aqueous media. Here, we investigate the sequence GVG(VPGVG)3 over a wide range of temperatures (below, around, and above the LCST) and peptide concentrations employing all-atom molecular dynamics simulations, where we focus on the role of intra- and inter-peptide interactions. We begin by investigating the structural properties of a single peptide that demonstrates a hydrophobic collapse with temperature, albeit moderate, as the sequence length is short. We observe a change in the interaction between two peptides from repulsive to attractive with temperature by evaluating the potential of mean force, indicating an LCST-like behaviour. Next, we explore dynamical and structural properties of peptides in multi-chain systems. We report the formation of dynamical aggregates with coil-like conformation, in which Val central residues play an important role. Moreover, the lifetime of contacts between chains strongly depends on the temperature and can be described by a power-law decay that is consistent with the LCST-like behaviour. Finally, the peptide translational and internal motion are slowed down by an increase in the peptide concentration and temperature.

biophysics↗