Flexible selection of the solute region in replica exchange with solute tempering: Application to protein-folding simulations

Abstract

Replica-exchange molecular dynamics (REMD) and their variants have been widely used in simulations of the biomolecular structure and dynamics. Replica exchange with solute tempering (REST) is one of the methods where temperature of a pre-defined solute molecule is exchanged between replicas, while solvent temperatures in all the replicas are kept constant. REST greatly reduces the number of replicas compared to the temperature REMD, while replicas at low temperatures are often trapped under their conditions, interfering with the conformational sampling. Here, we introduce a new scheme of REST, referred to as generalized REST (gREST), where the solute region is defined as a part of a molecule or a part of the potential energy terms, such as the dihedral-angle energy term or Lennard-Jones energy term. We applied this new method to folding simulations of a β-hairpin (16 residues) and a Trp-cage (20 residues) in explicit water. The protein dihedral-angle energy term is chosen as the solute region in the simulations. gREST reduces the number of replicas necessary for good random walks in the solute-temperature space and covers a wider conformational space compared to the conventional REST2. Considering the general applicability, gREST should become a promising tool for the simulations of protein folding, conformational dynamics, and an drug design.

High resolution ensemble description of metamorphic and intrinsically disordered proteins using an efficient hybrid parallel tempering scheme

“…The REST2 simulations sample the folded structure of TRP-cage ( Fig. 2B) and β-hairpin (Ref 24 ) at around 300 ns. Moreover, only 1-2 replicas out of 8 replicas are independently folded in these simulations ( Fig.…”

“…Moreover, only 1-2 replicas out of 8 replicas are independently folded in these simulations ( Fig. S5 and Ref 24 ). Free energy landscapes, as functions RMSD and radius of gyration, of the conformations sampled by the lowest temperature replica of TRP-cage simulations are presented in for REHT and REST2 in Fig.…”

“…The systems were also neutralized with physiological concentration of NaCl (0.15M). For the topological parameters of fast folding proteins, we used Amberff14SB in order to faithfully compare the efficiency with earlier REST2 and gREST simulations, 24 whereas for all the rest of the systems (alanine dipeptide, His-5 and RFA-H), Charmm36m 39 force field was used.…”

“…Originally developed in 1950s, 1 molecular dynamics (MD) simulation technique has come a long way since its first application on biological molecule in 1977. 1,2 With wide-range of applications, MD simulations are now routinely employed in important biomolecular characterization such as stability, flexibility, conformational changes, ligand binding and the effect of perturbations upon mutations, post-translational modifications and environmental changes. 3,4 Increased availability of high-performance computers in the last decade further expands its accessibility and allows simulating processes that take longer than microsecond timescales 5,6 and involve billions of atoms.…”

“…Inclusion of a subset of random water molecules to the tempering central group improves the mixing but at the expense of poor scaling with the system size. 23 More recently, a generalized version of the REST (gREST) that scales the Hamiltonian based on particles as well as energy terms has also been introduced, 24 which further reduces the number of replicas and alleviates the scalability issues to a large extent. However, as the extent of tempering is limited to few energy terms, the method requires longer time to converge on the conformational sampling.…”