Coarse-grained UNRES Force Field Research Articles

Assessment of Two Restraint Potentials for Coarse-Grained Chemical-Cross-Link-Assisted Modeling of Protein Structures.

The influence of distance restraints from chemical cross-link mass spectroscopy (XL-MS) on the quality of protein structures modeled with the coarse-grained UNRES force field was assessed by using a protocol based on multiplexed replica exchange molecular dynamics, in which both simulated and experimental cross-link restraints were employed, for 23 small proteins. Six cross-links with upper distance boundaries from 4 Å to 12 Å (azido benzoic acid succinimide (ABAS), triazidotriazine (TATA), succinimidyldiazirine (SDA), disuccinimidyl adipate (DSA), disuccinimidyl glutarate (DSG), and disuccinimidyl suberate (BS3)) and two types of restraining potentials ((i) simple flat-bottom Lorentz-like potentials dependent on side chain distance (all cross-links) and (ii) distance- and orientation-dependent potentials determined based on molecular dynamics simulations of model systems (DSA, DSG, BS3, and SDA)) were considered. The Lorentz-like potentials with properly set parameters were found to produce a greater number of higher-quality models compared to unrestrained simulations than the MD-based potentials, because the latter can force too long distances between side chains. Therefore, the flat-bottom Lorentz-like potentials are recommended to represent cross-link restraints. It was also found that significant improvement of model quality upon the introduction of cross-link restraints is obtained when the sum of differences of indices of cross-linked residues exceeds 150.

Long-Time Dynamics of Selected Molecular-Motor Components Using a Physics-Based Coarse-Grained Approach.

Molecular motors are essential for the movement and transportation of macromolecules in living organisms. Among them, rotatory motors are particularly efficient. In this study, we investigated the long-term dynamics of the designed left-handed alpha/alpha toroid (PDB: 4YY2), the RBM2 flagellum protein ring from Salmonella (PDB: 6SD5), and the V-type Na+-ATPase rotor in Enterococcus hirae (PDB: 2BL2) using microcanonical and canonical molecular dynamics simulations with the coarse-grained UNRES force field, including a lipid-membrane model, on a millisecond laboratory time scale. Our results demonstrate that rotational motion can occur with zero total angular momentum in the microcanonical regime and that thermal motions can be converted into net rotation in the canonical regime, as previously observed in simulations of smaller cyclic molecules. For 6SD5 and 2BL2, net rotation (with a ratcheting pattern) occurring only about the pivot of the respective system was observed in canonical simulations. The extent and direction of the rotation depended on the initial conditions. This result suggests that rotatory molecular motors can convert thermal oscillations into net rotational motion. The energy from ATP hydrolysis is required probably to set the direction and extent of rotation. Our findings highlight the importance of molecular-motor structures in facilitating movement and transportation within living organisms.

Long-time scale simulations of virus-like particles from three human-norovirus strains.

The dynamics of the virus like particles (VLPs) corresponding to the GII.4 Houston, GII.2 SMV, and GI.1 Norwalk strains of human noroviruses (HuNoV) that cause gastroenteritis was investigated by means of long-time (about 30 μs in the laboratory timescale) molecular dynamics simulations with the coarse-grained UNRES force field. The main motion of VLP units turned out to be the bending at the junction between the P1 subdomain (that sits in the VLP shell) and the P2 subdomain (that protrudes outside) of the major VP1 protein, this resulting in a correlated wagging motion of the P2 subdomains with respect to the VLP surface. The fluctuations of the P2 subdomain were found to be more pronounced and the P2 domain made a greater angle with the normal to the VLP surface for the GII.2 strain, which could explain the inability of this strain to bind the histo-blood group antigens (HBGAs).

Introduction of a bounded penalty function in contact-assisted simulations of protein structures to omit false restraints.

Contact-assisted simulations, the contacts being predicted or determined experimentally, have become very important in the determination of the structures of proteins and other biological macromolecules. In this work, the effect of contact-distance restraints on the simulated structures was investigated with the use of multiplexed replica exchange simulations with the coarse-grained UNRES force field. A modified bounded flat-bottom restraint function that does not generate a gradient when a restraint cannot be satisfied was implemented. Calculations were run with (i) a set of four small proteins, with contact restraints derived from experimental structures, and (ii) selected CASP11 and CASP12 targets, with restraints as used at prediction time. The bounded penalty function largely omitted false contacts, which were usually inconsistent. It was found that at least 20% of correct contacts must be present in the restraint set to improve model quality with respect to unrestrained simulations. © 2019 Wiley Periodicals, Inc.

Prediction of protein structure with the coarse-grained UNRES force field assisted by small X-ray scattering data and knowledge-based information.

A new approach to assisted protein-structure prediction has been proposed, which is based on running multiplexed replica exchange molecular dynamics simulations with the coarse-grained UNRES force field with restraints derived from knowledge-based models and distance distribution from small angle X-ray scattering (SAXS) measurements. The latter restraints are incorporated into the target function as a maximum-likelihood term that guides the shape of the simulated structures towards that defined by SAXS. The approach was first verified with the 1KOY protein, for which the distance distribution was calculated from the experimental structure, and subsequently used to predict the structures of 11 data-assisted targets in the CASP12 experiment. Major improvement of the GDT_TS was obtained for 2 targets, minor improvement for other 2 while, for 6 target GDT_TS deteriorated compared with that calculated for predictions without the SAXS data, partly because of assuming a wrong multimeric state (for Ts866) or because the crystal conformation was more compact than the solution conformation (for Ts942). Particularly good results were obtained for Ts909, in which use of SAXS data resulted in the selection of a correctly packed trimer and, subsequently, increased the GDT_TS of monomer prediction. It was found that running simulations with correct oligomeric state is essential for the success in SAXS-data-assisted prediction.

Ergodicity and model quality in template-restrained canonical and temperature/Hamiltonian replica exchange coarse-grained molecular dynamics simulations of proteins

Molecular simulations restrained to single or multiple templates are commonly used in protein-structure modeling. However, the restraints introduce additional barriers, thus impairing the ergodicity of simulations, which can affect the quality of the resulting models. In this work, the effect of restraint types and simulation schemes on ergodicity and model quality was investigated by performing template-restrained canonical molecular dynamics (MD), multiplexed replica-exchange molecular dynamics, and Hamiltonian replica exchange molecular dynamics (HREMD) simulations with the coarse-grained UNRES force field on nine selected proteins, with pseudo-harmonic log-Gaussian (unbounded) or Lorentzian (bounded) restraint functions. The best ergodicity was exhibited by HREMD. It has been found that non-ergodicity does not affect model quality if good templates are used to generate restraints. However, when poor-quality restraints not covering the entire protein are used, the improved ergodicity of HREMD can lead to significantly improved protein models. © 2017 Wiley Periodicals, Inc.

Role of the sulfur to α-carbon thioether bridges in thurincin H

Thurincin H is a small protein produced by Bacillus thuringiensis SF361 with gram-positive antimicrobial properties. The toxins produced by B. thuringiensis are widely used in the agriculture as, e.g. natural preservatives in dairy products. The structure of thurincin H possesses four covalent sulfur to -carbon bonds that involve the cysteine side-chains; these bonds are probably responsible for the shape and stability of the protein and, thereby, for its antimicrobial properties. To examine the influence of the formation of the sulfur-carbon bonds on the folding pathways and stability of the protein, a series of canonical and multiplexed replica-exchange simulations with the coarse-grained UNRES force field was carried out without and with distance restraints imposed on selected S-C atom pairs. It was found that the order of the formation and breaking of the S-C thioether bonds significantly impacts on the foldability and stability of the thurincin H. It was also observed that thioether bridges play a major role in stabilizing the global fold of the protein, although it significantly diminishes the entropy of the system. The maximum foldability of thurincin H was observed in the presence of the optimal set of three out of four thioether bridges. Thus, the results suggest that the presence of ThnB enzyme and other agents that catalyze the formation of thioether bridges can be essential for correct folding of thurincin H and that the formation of the fourth bridge does not seem to facilitate folding; instead, it seems to rigidify the loop and prevent proteolysis.

Studies of conformational changes of an arginine-binding protein from Thermotoga maritima in the presence and absence of ligand via molecular dynamics simulations with the coarse-grained UNRES force field.

The arginine-binding protein (ArgBP) from the hyperthermophilic eubacterium Thermotoga maritima (TmArgBP) is responsible for arginine transport through the bacterial cell membrane. The protein binds a single molecule of L-arginine, which results in conformational changes due to hinge bending. Thereby, TmArgBP acquires one of two possible conformations: open (without the presence of the arginine ligand) and closed (in the presence of the arginine ligand). Here we report a molecular dynamics study of the influence of the presence or absence of the ligand on the dynamics of TmArgBP, using the coarse-grained UNRES force field. The results of our studies indicate that binding of the arginine ligand promotes a closed conformation, which agrees with experimental data. However, the sensitivity of the TmArgBP conformation to the presence of arginine decreases and the protein becomes more flexible with increasing temperature, which might be related to the functionality of this protein in the thermophilic organism T. maritima.

PDZ Binding to the BAR Domain of PICK1 is Elucidated by Coarse-grained Molecular Dynamics

A key regulator of α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor traffic, PICK1 is known to interact with over 40 other proteins, including receptors, transporters and ionic channels, and to be active mostly as a homodimer. The current lack of a complete PICK1 structure determined at atomic resolution hinders the elucidation of its functional mechanisms. Here, we identify interactions between the component PDZ and BAR domains of PICK1 by calculating possible binding sites for the PDZ domain of PICK1 (PICK1-PDZ) to the homology-modeled, crescent-shaped dimer of the PICK1-BAR domain using multiplexed replica-exchange molecular dynamics (MREMD) and canonical molecular dynamics simulations with the coarse-grained UNRES force field. The MREMD results show that the preferred binding site for the single PDZ domain is the concave cavity of the BAR dimer. A second possible binding site is near the N-terminus of the BAR domain that is linked directly to the PDZ domain. Subsequent short canonical molecular dynamics simulations used to determine how the PICK1-PDZ domain moves to the preferred binding site on the BAR domain of PICK1 revealed that initial hydrophobic interactions drive the progress of the simulated binding. Thus, the concave face of the BAR dimer accommodates the PDZ domain first by weak hydrophobic interactions and then the PDZ domain slides to the center of the concave face, where more favorable hydrophobic interactions take over.

Implementation of Molecular Dynamics and Its Extensions with the Coarse-Grained UNRES Force Field on Massively Parallel Systems: Toward Millisecond-Scale Simulations of Protein Structure, Dynamics, and Thermodynamics

We report the implementation of our united-residue UNRES force field for simulations of protein structure and dynamics with massively parallel architectures. In addition to coarse-grained parallelism already implemented in our previous work, in which each conformation was treated by a different task, we introduce a fine-grained level in which energy and gradient evaluation are split between several tasks. The Message Passing Interface (MPI) libraries have been utilized to construct the parallel code. The parallel performance of the code has been tested on a professional Beowulf cluster (Xeon Quad Core), a Cray XT3 supercomputer, and two IBM BlueGene/P supercomputers with canonical and replica-exchange molecular dynamics. With IBM BlueGene/P, about 50 % efficiency and 120-fold speed-up of the fine-grained part was achieved for a single trajectory of a 767-residue protein with use of 256 processors/trajectory. Because of averaging over the fast degrees of freedom, UNRES provides an effective 1000-fold speed-up compared to the experimental time scale and, therefore, enables us to effectively carry out millisecond-scale simulations of proteins with 500 and more amino-acid residues in days of wall-clock time.

Relation between Free Energy Landscapes of Proteins and Dynamics

By examining the molecular dynamics (MD) of protein folding trajectories, generated with the coarse-grained UNRES force field, for the B-domain of staphylococcal protein A and the triple β-strand WW domain from the Formin binding protein 28 (FBP), by principal component analysis (PCA), it is demonstrated how different free energy landscapes (FELs) and folding pathways of trajectories can be, even though they appear to be very similar by visual inspection of the time-dependence of the root-mean-square deviation (rmsd). Approaches to determine the minimal dimensionality of FELs for a correct description of protein folding dynamics are discussed. The correlation between the amplitude of the fluctuations of proteins and the dimensionality of the FELs is shown. The advantage of internal coordinate PCA over Cartesian PCA for small proteins is also illustrated.