Replica exchanging self-guided Langevin dynamics for efficient and accurate conformational sampling

Abstract

This work presents a replica exchanging self-guided Langevin dynamics (RXSGLD) simulation method for efficient conformational searching and sampling. Unlike temperature-based replica exchanging simulations, which use high temperatures to accelerate conformational motion, this method uses self-guided Langevin dynamics (SGLD) to enhance conformational searching without the need to elevate temperatures. A RXSGLD simulation includes a series of SGLD simulations, with simulation conditions differing in the guiding effect and/or temperature. These simulation conditions are called stages and the base stage is one with no guiding effect. Replicas of a simulation system are simulated at the stages and are exchanged according to the replica exchanging probability derived from the SGLD partition function. Because SGLD causes less perturbation on conformational distribution than high temperatures, exchanges between SGLD stages have much higher probabilities than those between different temperatures. Therefore, RXSGLD simulations have higher conformational searching ability than temperature based replica exchange simulations. Through three example systems, we demonstrate that RXSGLD can generate target canonical ensemble distribution at the base stage and achieve accelerated conformational searching. Especially for large systems, RXSGLD has remarkable advantages in terms of replica exchange efficiency, conformational searching ability, and system size extensiveness.

Efficiently computing pathway free energies: New approaches based on chain-of-replica and Non-Boltzmann Bennett reweighting schemes

“…This is not based simply on efficiency, but also on the fact that numerous enhanced sampling methods have been developed specifically for classical simulations. [69][70][71][72][73][74][75][76][77] The other requirement is the accurate description of intra-and intermolecular interactions; here, the use of a QM-based Hamiltonian is desirable if not essential, in particular if chemical reactions are to be described. While satisfying these two requirements is extremely difficult, even for MM based approaches, they create a quandary when QM or QM/MM is used.…”

The carbon monoxide dehydrogenase accessory protein CooJ is a histidine-rich multidomain dimer containing an unexpected Ni(II)-binding site

“…All missing atom coordinates were built with CHARMM using internal coordinates, and the structure was energy-minimized down to a gradient of 0.1 kcal/mol/Å. With 100 residues unresolved in the dimer, the resulting initial model needed a powerful algorithm able to sample the conformational space of the protein like replica-exchanging self-guided Langevin dynamics (47). Self-guided Langevin dynamics enhances conformational search efficiency through acceleration of low frequency motions in a molecular system (48).…”

Tyrosine metabolism: identification of a key residue in the acquisition of prephenate aminotransferase activity by 1β aspartate aminotransferase

“…, enabling Lys12 to be stabilized in the vicinity of the prephenate. Still, a method to explore more conformational space is to use Replica eXchanging Self‐Guided Langevin Dynamics . Sixteen replicas were created starting from structure 1BKG_Preph_Mod and vacuum RXGLD simulations were run for 10 ns in the presence of restraints (see Experimental procedures).…”

“…A method to explore more conformational space is to use Replica eXchanging Self‐Guided Langevin Dynamics as implemented in CHARMM in the RXSGLD module . SGLD simulations enhance conformational search efficiency through acceleration of low frequency motions in a molecular system.…”