The calculation of thermodynamic properties of biochemical systems typically requires the use of resource-intensive molecular simulation methods. One example thereof is the thermodynamic profiling of hydration sites, i.e. high-probability locations for water molecules on the protein surface, which play an essential role in protein-ligand associations and must therefore be incorporated in the prediction of binding poses and affinities. To replace time-consuming simulations in hydration site predictions, we developed two different types of deep neural-network models aiming to predict hydration site data. In the first approach, meshed 3D images are generated representing the interactions between certain molecular probes placed on regular 3D grids, encompassing the binding pocket, with the static protein. These molecular interaction fields are mapped to the corresponding 3D image of hydration occupancy using a neural network based on an U-Net architecture. In a second approach, hydration occupancy and thermodynamics were predicted point-wise using a neural network based on fully-connected layers. In addition to direct protein interaction fields, the environment of each grid point was represented using moments of a spherical harmonics expansion of the interaction properties of nearby grid points. Application to structure-activity relationship analysis and protein-ligand pose scoring demonstrates the utility of the predicted hydration information.
The molecular mechanism of the solvent motion that is required to instigate the protein structural relaxation above a critical hydration level or transition temperature has yet to be determined. In this work we use quasi-elastic neutron scattering (QENS) and molecular dynamics simulation to investigate hydration water dynamics near a greatly simplified protein surface. We consider the hydration water dynamics near the completely deuterated N-acetyl-leucine-methylamide (NALMA) solute, a hydrophobic amino acid side chain attached to a polar blocked polypeptide backbone, as a function of concentr…
Protein-protein binding enables orderly and lawful biological self-organization, and is therefore considered a miracle of nature. Protein-protein binding is steered by electrostatic forces, hydrogen bonding, van der Waals force, and hydrophobic interactions. Among these physical forces, only the hydrophobic interactions can be considered as long-range intermolecular attractions between proteins in intracellular and extracellular fluid. Low-entropy regions of hydration shells around proteins drive hydrophobic attraction among them that essentially coordinate protein-protein docking in rotationa…
The low-frequency collective vibrational modes in proteins as well as the protein-water interface have been suggested as dominant factors controlling the efficiency of biochemical reactions and biological energy transport. It is thus crucial to uncover the mystery of hydration structure and dynamics as well as their coupling to collective motions of proteins in aqueous solutions. Here we report dielectric properties of aqueous bovine serum albumin protein solutions as a model system using an extremely sensitive dielectric spectrometer with frequencies spanning from megahertz to terahertz. The …
Since the pioneering works of Pethig, Grant and Wuthrich on protein hydration layer, many studies have been devoted to find out if there are any general and universal characteristic features that can distinguish water molecules inside the protein hydration layer from bulk. Given that the surface itself varies from protein to protein, and that each surface facing the water is heterogeneous, search for universal features has been elusive. Here, we perform atomistic molecular dynamics simulation in order to propose and demonstrate that such defining characteristics can emerge if we look not at av…
The infectivity of SARS-CoV-2 depends on the binding affinity of the receptor-binding domain (RBD) of the spike protein with the angiotensin converting enzyme 2 (ACE2) receptor. The calculated RBD-ACE2 binding energies indicate that the difference in transmission efficiency of SARS-CoV-2 variants cannot be fully explained by electrostatic interactions, hydrogen-bond interactions, van der Waals interactions, internal energy, and nonpolar solvation energies. Here, we demonstrate that low-entropy regions of hydration shells around proteins drive hydrophobic attraction between shape-matched low-en…
We investigate dynamical coupling between water and amino acid side-chain residues in solvation dynamics by selecting residues often used as natural probes, namely tryptophan, tyrosine and histidine, located at different positions on protein surface and having various degrees of solvent exposure. Such differently placed residues are found to exhibit different timescales of relaxation. The total solvation response, as measured by the probe is decomposed in terms of its interactions with (i) protein core, (ii) side-chain atoms and (iii) water molecules. Significant anti cross-correlations among …
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 largest increase for lowest hydrations and highest frequencies. For both oxidation states the THz response rapidly increases with hydration saturating above ~25% (g H2O/g protein). Quasi-harmonic vibrational modes and dipole-dipole correlation functions are calculated from molecular dy…
When the hydration shell of a protein is filled with at least 0.6 gram of water per gram of protein, a significant anti-correlation between the vibrational free energy and the potential energy of energy-minimized conformers is observed. This means that low potential energy, well-hydrated, protein conformers tend to be more rigid than high-energy ones. On the other hand, in the case of CASP target 624, when its hydration shell is filled, a significant average energy gap is observed between the crystal structure and the best conformers proposed during the prediction experiment, strongly suggesti…
The hydration thermodynamics of the GXG tripeptide relative to the reference GGG is often used to define the conditional hydration contribution of X. This quantity or the hydration thermodynamics of a small molecule analog of the side-chain or some combination of such estimates, have anchored the interpretation of seminal experiments on protein stability and folding. We show that such procedures to model protein hydration have significant limitations. We study the conditional hydration thermodynamics of the isoleucine side-chain in an extended pentapeptide and in helical deca-peptides, using a…
ProteinGuide: On-the-fly property guidance for protein sequence generative models
Department of Electrical Engineering and Computer Sciences, University of California, Berkeley（电气工程与计算机科学系，加州大学伯克利分校）；Center for Computational Biology, University of California, Berkeley（计算生物学中心，加州大学伯克利分校）；Department of Molecular and Cell Biology, University of California, Berkeley（分子与细胞生物学系，加州大学伯克利分校）；Innovative Genomics Institute, University of California, Berkeley（创新基因组研究所，加州大学伯克利分校）；Howard Hughes Medical Institute, University of California, Berkeley（霍华德·休斯医学研究所，加州大学伯克利分校）
This paper explores the reduced form of horse cytochrome c confined in reverse micelles (RM) of so-dium bis-(2-ethylhexyl) sulfosuccinate (AOT) in isooctane by molecular dynamics simulation. RMs of two sizes were constructed at a water content of Wo = [H2O]/[AOT] = 5.5 and 9.1. Our results show that the protein secondary structure and the heme conformation both depend on micellar hydration. At low hydration, the protein structure and the heme moiety remain stable, whereas at high water content the protein becomes unstable and starts to unfold. At Wo = 9.1, according to the X-ray structure, con…
Sucralose is a commonly employed artificial sweetener that appears to destabilize protein native structures. This is in direct contrast to the bio-preservative nature of its natural counterpart, sucrose, which enhances the stability of biomolecules against environmental stress. We have further explored the molecular interactions of sucralose as compared to sucrose to illuminate the origin of the differences in their bio-preservative efficacy. We show that the mode of interactions of sucralose and sucrose in bulk solution differ subtly using hydration dynamics measurement and computational simu…
Previous kinetic models had assumed that the reaction medium was reacting at random and without a turnover associated to thermodynamics exchanges, with a rigid active site on the enzyme. The experimental studies show that coupling factor 1 (CF1) from spinach chloroplasts has latent ATPase activity, which become expressed after heat-treatment and incubation with calcium. The sigmoidal kinetics observed on the competitive effect of glycerol on water saturating a protein, suggests that the role of the hydration shell in the catalytic mechanism of the CF1-ATPase, modify the number of water molecul…
Native extracellular matrices (ECMs), such as those of the human brain and other neural tissues, exhibit networks of molecular interactions between specific matrix proteins and other tissue components. Guided by these naturally self-assembling supramolecular systems, we have designed a matrix-derived protein chimera that contains a laminin globular-like (LG) domain fused to an elastin-like polypeptide (ELP). All-atom, classical molecular dynamics simulations of our designed laminin-elastin fusion protein reveal temperature-dependent conformational changes, in terms of secondary structure compo…
In response to cold stress, Drosophila Melanogaster increase their expression of Frost, a candidate gene involved in cold response. The direct role of Frost in cold tolerance is yet to be determined, and its importance for survival in cold environments has been questioned. In this study, I attempt to better understand the molecular machinery of Frost by selecting for its protein in fly lysate knowing only its RNA has been found. Detection of Frost expression and subsequently studying its protein will hopefully lead to enhanced comprehension of cold responses in insects, which is the long-term …
In addition to the biologically active monomer of the protein Insulin circulating in human blood, the molecule also exists in dimeric and hexameric forms that are used as storage. The Insulin monomer contains two distinct surfaces, namely the dimer forming surface (DFS) and the hexamer forming surface (HFS) that are specifically designed to facilitate the formation of the dimer and the hexamer, respectively. In order to characterize the structural and dynamical behaviour of interfacial water molecules near these two surfaces (DFS and HFS), we performed atomistic molecular dynamics simulations …
Molecular simulations to investigate the impact of N6-methylation in RNA recognition: Improving accuracy and precision of binding free energy prediction
The influence of three well-known disaccharides, namely trehalose, maltose and sucrose, on some structural and dynamical properties of lysozyme has been investigated by means of molecular dynamics computer simulations in the 37-60 wt % concentration range. The effects of sugars on the protein conformation are found relatively weak, in agreement with the preferential hydration of lysozyme. Conversely, sugars seem to increase significantly the relaxation times of the protein. These effects are shown to be correlated to the fractional solvent accessibilities of lysozyme residues and further suppo…
Czech Institute of Informatics, Robotics and Cybernetics, Czech Technical University（捷克信息学、机器人学与自动化研究所，捷克技术大学）；Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences（捷克科学院有机化学与生物化学研究所）；School of Biological Sciences, Seoul National University（首尔国立大学生物科学学院）；Interdisciplinary Program in Bioinformatics, Seoul National University（首尔国立大学生物信息学跨学科项目）；Institute of Molecular Biology and Genetics, Seoul National University（首尔国立大学分子生物学与遗传学研究所）；Artificial Intelligence Institute, Seoul National University（首尔国立大学人工智能研究所）；CSAIL, Massachusetts Institute of Technology（麻省理工学院计算机科学与人工智能实验室）；Qminers
To address the large gap between time scales that can be easily reached by molecular simulations and those required to understand protein dynamics, we propose a rapid self-consistent approximation of the side chain free energy at every integration step. In analogy with the adiabatic Born-Oppenheimer approximation for electronic structure, the protein backbone dynamics are simulated as preceding according to the dictates of the free energy of an instantaneously-equilibrated side chain potential. The side chain free energy is computed on the fly, allowing the protein backbone dynamics to travers…
Coarse-graining of fully atomistic molecular dynamics simulations is a long-standing goal in order to allow the description of processes occurring on biologically relevant timescales. For example, the prediction of pathways, rates and rate-limiting steps in protein-ligand unbinding is crucial for modern drug discovery. To achieve the enhanced sampling, we first perform dissipation-corrected targeted molecular dynamics simulations, which yield free energy and friction profiles of the molecular process under consideration. In a second step, we use these fields to perform temperature-boosted Lang…
We investigate the role of order/disorder transitions in alchemical simulations of protein-ligand absolute binding free energies. We show, in the context of a potential of mean force description, that for a benchmarking system (the complex between the L99A mutant of T4 lysozyme and 3-iodotoluene) and for a more challenging system relevant for medicinal applications (the complex of the farnesoid X receptor and inhibitor 26 from a recent D3R challenge) that order/disorder transitions can significantly hamper Hamiltonian replica exchange sampling efficiency and slow down the rate of equilibration…
