SUMMARY: The UNited RESisdue (UNRES) package for coarse-grained simulations, which has recently been optimized to treat large protein systems, has been implemented on Graphical Processor Units (GPUs). An over 100-time speed-up of the GPU code (run on an NVIDIA A100) with respect to the sequential code and an 8.5 speed-up with respect to the parallel Open Multi-Processing (OpenMP) code (run on 32 cores of 2 AMD EPYC 7313 Central Processor Units (CPUs)) has been achieved for large proteins (with size over 10 000 residues). Due to the averaging over the fine-grain degrees of freedom, 1 time unit of UNRES simulations is equivalent to about 1000 time units of laboratory time; therefore, millisecond time scale of large protein systems can be reached with the UNRES-GPU code. AVAILABILITY AND IMPLEMENTATION: The source code of UNRES-GPU along with the benchmarks used for tests is available at https://projects.task.gda.pl/eurohpcpl-public/unres.

MOTIVATION: The majority of the proteins in living organisms occur as homo- or hetero-multimeric structures. Although there are many tools to predict the structures of single-chain proteins or protein complexes with small ligands, peptide-protein and protein-protein docking is more challenging. In this work, we utilized multiplexed replica-exchange molecular dynamics (MREMD) simulations with the physics-based heavily coarse-grained UNRES model, which provides more than a 1000-fold simulation speed-up compared with all-atom approaches to predict structures of protein complexes. RESULTS: We present a new protein-protein and peptide-protein docking functionality of the UNRES package, which includes a variable degree of conformational flexibility. UNRES-Dock protocol was tested on a set of 55 complexes with size from 43 to 587 amino-acid residues, showing that structures of the complexes can be predicted with good quality, if the sampling of the conformational space is sufficient, especially for flexible peptide-protein systems. The developed automatized protocol has been implemented in the standalone UNRES package and in the UNRES server. AVAILABILITY AND IMPLEMENTATION: UNRES server: http://unres-server.chem.ug.edu.pl; UNRES package and data used in testing of UNRES-Dock: http://unres.pl. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Participating as the Cornell-Gdansk group, we have used our physics-based coarse-grained UNited RESidue (UNRES) force field to predict protein structure in the 11th Community Wide Experiment on the Critical Assessment of Techniques for Protein Structure Prediction (CASP11). Our methodology involved extensive multiplexed replica exchange simulations of the target proteins with a recently improved UNRES force field to provide better reproductions of the local structures of polypeptide chains. All simulations were started from fully extended polypeptide chains, and no external information was included in the simulation process except for weak restraints on secondary structure to enable us to finish each prediction within the allowed 3-week time window. Because of simplified UNRES representation of polypeptide chains, use of enhanced sampling methods, code optimization and parallelization and sufficient computational resources, we were able to treat, for the first time, all 55 human prediction targets with sizes from 44 to 595 amino acid residues, the average size being 251 residues. Complete structures of six single-domain proteins were predicted accurately, with the highest accuracy being attained for the T0769, for which the CαRMSD was 3.8 Å for 97 residues of the experimental structure. Correct structures were also predicted for 13 domains of multi-domain proteins with accuracy comparable to that of the best template-based modeling methods. With further improvements of the UNRES force field that are now underway, our physics-based coarse-grained approach to protein-structure prediction will eventually reach global prediction capacity and, consequently, reliability in simulating protein structure and dynamics that are important in biochemical processes. AVAILABILITY AND IMPLEMENTATION: Freely available on the web at http://www.unres.pl/ CONTACT: [email protected].

Based on the results of our recent work on the determination of the potentials of mean force of pairs of models of amino-acid side chains in water, in this work we make an attempt at introducing temperature-dependent side chain - side chain interaction potentials in our coarse-grained UNRES energy function. For hydrophobic pairs as well as oppositely-charged pairs, two functional forms are introduced, one of which implies a linear dependence of the free energy of interactions on temperature and the other one a hyperbolic-tangent dependence. The free energy of the interactions of other pairs is assumed to be independent of temperature. With the example of the N-terminal part of the B-domain of staphylococcal protein A, we demonstrate that, with this temperature dependence, the radius of gyration and the root-mean-square deviation from the native structure grow less steeply with temperature and the heat-capacity peak is lower than that obtained with temperature-independent side chain - side chain potentials. This demonstrates that ignoring the increase of the strength of hydrophobic interactions with increasing temperature in coarse-grained force fields is likely to result in grossly wrong predictions of the thermodynamics of folding and of the process of thermal unfolding made with such force fields.

United-residue models of polypeptide chains [3, 5, 19-22, 24, 31, 33] have long been of interest, because they enable one to carry out global conformational searches of proteins in real time, which in turn can facilitate ab initio protein structure predictions based solely on Anfinsen's thermodynamic hypothesis [1], according to which the native structure of a protein is a global minimum of its potential energy surface [32]. In the last few years, we developed a united-residue force field [20-22, 24], hereafter referred to as UNRES, in which a polypeptide chain is represented by a sequence of α-carbon (Cα) atoms linked by virtual bonds with attached united side chains (SC) and united peptide groups (p) located in the middle between the consecutive α-carbons (Figure 1). Only the united peptide groups and united side chains serve as interaction sites, the α-carbons serving to define the geometry.