Abstract
A server implementation of the UNRES package (http://www.unres.pl) for coarse-grained simulations of protein structures with the physics-based UNRES model, coined a name UNRES server, is ...presented. In contrast to most of the protein coarse-grained models, owing to its physics-based origin, the UNRES force field can be used in simulations, including those aimed at protein-structure prediction, without ancillary information from structural databases; however, the implementation includes the possibility of using restraints. Local energy minimization, canonical molecular dynamics simulations, replica exchange and multiplexed replica exchange molecular dynamics simulations can be run with the current UNRES server; the latter are suitable for protein-structure prediction. The user-supplied input includes protein sequence and, optionally, restraints from secondary-structure prediction or small x-ray scattering data, and simulation type and parameters which are selected or typed in. Oligomeric proteins, as well as those containing D-amino-acid residues and disulfide links can be treated. The output is displayed graphically (minimized structures, trajectories, final models, analysis of trajectory/ensembles); however, all output files can be downloaded by the user. The UNRES server can be freely accessed at http://unres-server.chem.ug.edu.pl.
Molecular dynamics (MD) is an invaluable tool with which to study protein folding in silico. Although just a few years ago the dynamic behavior of a protein molecule could be simulated only in the ...neighborhood of the experimental conformation (or protein unfolding could be simulated at high temperature), the advent of distributed computing, new techniques such as replica-exchange MD, new approaches (based on, e.g., the stochastic difference equation), and physics-based reduced models of proteins now make it possible to study protein-folding pathways from completely unfolded structures. In this review, we present algorithms for MD and their extensions and applications to protein-folding studies, using all-atom models with explicit and implicit solvent as well as reduced models of polypeptide chains.
Coarse-grained models are useful tools to investigate the structural and thermodynamic properties of biomolecules. They are obtained by merging several atoms into one interaction site. Such ...simplified models try to capture as much as possible information of the original biomolecular system in all-atom representation but the resulting parameters of these coarse-grained force fields still need further optimization. In this paper, a force field optimization method, which is based on maximum-likelihood fitting of the simulated to the experimental conformational ensembles and least-squares fitting of the simulated to the experimental heat-capacity curves, is applied to optimize the Nucleic Acid united-RESidue 2-point (NARES-2P) model for coarse-grained simulations of nucleic acids recently developed in our laboratory. The optimized NARES-2P force field reproduces the structural and thermodynamic data of small DNA molecules much better than the original force field.
The SARS-CoV-2 virus, commonly known as COVID-19, first occurred in December 2019 in Wuhan, Hubei Province, China. Since then, it has become a tremendous threat to human health. With a pandemic ...threat, it is in the significant interest of the scientific world to establish its method of infection. In this manuscript, we combine knowledge of the infection mechanism with theoretical methods to answer the question of the virus's selectivity. We proposed a two-stage infection mechanism. In the first step, the virus interacts with the ACE2 receptor, with the "proper strength". When the interaction is too strong, the virus will remain in an "improper position"; if the interaction is too weak, the virus will "run away" from the cell. We also indicated three residues (positions 30, 31, and 353) located on the ACE2 protein-binding interface, which seems to be crucial for successful infection. Our results indicate that these residues are necessary for the initiation of the infection process.
We report the application of Langevin dynamics to the physics-based united-residue (UNRES) force field developed in our laboratory. Ten trajectories were run on seven proteins PDB ID codes 1BDD (α; ...46 residues), 1GAB (α; 47 residues), 1LQ7 (α; 67 residues), 1CLB (α; 75 residues), 1E0L (β; 28 residues), and 1E0G (α+β; 48 residues), and 1IGD (α+β; 61 residues) with the UNRES force field parameterized by using our recently developed method for obtaining a hierarchical structure of the energy landscape. All α-helical proteins and 1E0G folded to the native-like structures, whereas 1IGD and 1E0L yielded mostly nonnative α-helical folds although the native-like structures are lowest in energy for these two proteins, which can be attributed to neglecting the entropy factor in the current parameterization of UNRES. Average folding times for successful folding simulations were of the order of nanoseconds, whereas even the ultrafast-folding proteins fold only in microseconds, which implies that the UNRES time scale is approximately three orders of magnitude larger than the experimental time scale because the fast motions of the secondary degrees of freedom are averaged out. Folding with Langevin dynamics required 2-10 h of CPU time on average with a single AMD Athlon MP 2800+ processor depending on the size of the protein. With the advantage of parallel processing, this process leads to the possibility to explore thousands of folding pathways and to predict not only the native structure but also the folding scenario of a protein together with its quantitative kinetic and thermodynamic characteristics.
The physics-based UNRES coarse-grained force field for the simulations of protein structure and dynamics has been extended to treat membrane proteins. The lipid bilayer has been modeled by ...introducing a continuous nonpolar phase with the water-interface region of appropriate thickness. The potentials for average electrostatic and correlation interactions of the peptide groups have been rescaled to account for the reduction of the dielectric permittivity compared to the water phase and new potentials for protein side-chain–side-chain interactions inside and across the lipid phase have been introduced. The model was implemented in the UNRES package for coarse-grained simulations of proteins, and the package with the new functionality was tested for total energy conservation and thermostat behavior in microcanonical and canonical molecular dynamics simulations runs, respectively. The method was validated by running unrestricted ab initio blind-prediction tests of 10 short α-helical membrane proteins, all runs started from the extended structures. The modified UNRES force field was able to predict correctly the overall folds of the membrane proteins studied.
By using the maximum likelihood method for force-field calibration recently developed in our laboratory, which is aimed at achieving the agreement between the simulated conformational ensembles of ...selected training proteins and the corresponding ensembles determined experimentally at various temperatures, the physics-based coarse-grained UNRES force field for simulations of protein structure and dynamics was optimized with seven small training proteins exhibiting a variety of secondary and tertiary structures. Four runs of optimization, in which the number of optimized force-field parameters was gradually increased, were carried out, and the resulting force fields were subsequently tested with a set of 22 α-, 12 β-, and 12 α + β-proteins not used in optimization. The variant in which energy-term weights, local, and correlation potentials, side-chain radii, and anisotropies were optimized turned out to be the most transferable and outperformed all previous versions of UNRES on the test set.
We review the coarse-grained UNited RESidue (UNRES) force field for the simulations of protein structure and dynamics, which is being developed in our laboratory over the last several years. UNRES is ...a physics-based force field, the prototype of which is defined as a potential of mean force of polypeptide chains in water, where all the degrees of freedom except the coordinates of α-carbon atoms and side-chain centers have been integrated out. We describe the initial implementation of UNRES to protein-structure prediction formulated as a search for the global minimum of the potential-energy function and its subsequent molecular dynamics and extensions of molecular-dynamics implementation, which enabled us to study protein-folding pathways and thermodynamics, as well as to reformulate the protein-structure prediction problem as a search for the conformational ensemble with the lowest free energy at temperatures below the folding-transition temperature. Applications of UNRES to study biological problems are also described.
With the advance of experimental procedures obtaining chemical crosslinking information is becoming a fast and routine practice. Information on crosslinks can greatly enhance the accuracy of protein ...structure modeling. Here, we review the current state of the art in modeling protein structures with the assistance of experimentally determined chemical crosslinks within the framework of the 13th meeting of Critical Assessment of Structure Prediction approaches. This largest‐to‐date blind assessment reveals benefits of using data assistance in difficult to model protein structure prediction cases. However, in a broader context, it also suggests that with the unprecedented advance in accuracy to predict contacts in recent years, experimental crosslinks will be useful only if their specificity and accuracy further improved and they are better integrated into computational workflows.
Molecular dynamics with coarse-grained models is nowadays extensively used to simulate biomolecular systems at large time and size scales, compared to those accessible to all-atom molecular dynamics. ...In this review article, we describe the physical basis of coarse-grained molecular dynamics, the coarse-grained force fields, the equations of motion and the respective numerical integration algorithms, and selected practical applications of coarse-grained molecular dynamics. We demonstrate that the motion of coarse-grained sites is governed by the potential of mean force and the friction and stochastic forces, resulting from integrating out the secondary degrees of freedom. Consequently, Langevin dynamics is a natural means of describing the motion of a system at the coarse-grained level and the potential of mean force is the physical basis of the coarse-grained force fields. Moreover, the choice of coarse-grained variables and the fact that coarse-grained sites often do not have spherical symmetry implies a non-diagonal inertia tensor. We describe selected coarse-grained models used in molecular dynamics simulations, including the most popular MARTINI model developed by Marrink's group and the UNICORN model of biological macromolecules developed in our laboratory. We conclude by discussing examples of the application of coarse-grained molecular dynamics to study biologically important processes.
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