Dataset Information

Practical Protocols for Efficient Sampling of Kinase-Inhibitor Binding Pathways Using Two-Dimensional Replica-Exchange Molecular Dynamics.

ABSTRACT: Molecular dynamics (MD) simulations are increasingly used to study various biological processes such as protein folding, conformational changes, and ligand binding. These processes generally involve slow dynamics that occur on the millisecond or longer timescale, which are difficult to simulate by conventional atomistic MD. Recently, we applied a two-dimensional (2D) replica-exchange MD (REMD) method, which combines the generalized replica exchange with solute tempering (gREST) with the replica-exchange umbrella sampling (REUS) in kinase-inhibitor binding simulations, and successfully observed multiple ligand binding/unbinding events. To efficiently apply the gREST/REUS method to other kinase-inhibitor systems, we establish modified, practical protocols with non-trivial simulation parameter tuning. The current gREST/REUS simulation protocols are tested for three kinase-inhibitor systems: c-Src kinase with PP1, c-Src kinase with Dasatinib, and c-Abl kinase with Imatinib. We optimized the definition of kinase-ligand distance as a collective variable (CV), the solute temperatures in gREST, and replica distributions and umbrella forces in the REUS simulations. Also, the initial structures of each replica in the 2D replica space were prepared carefully by pulling each ligand from and toward the protein binding sites for keeping stable kinase conformations. These optimizations were carried out individually in multiple short MD simulations. The current gREST/REUS simulation protocol ensures good random walks in 2D replica spaces, which are required for enhanced sampling of inhibitor dynamics around a target kinase.

SUBMITTER: Shinobu A

PROVIDER: S-EPMC9099257 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Practical Protocols for Efficient Sampling of Kinase-Inhibitor Binding Pathways Using Two-Dimensional Replica-Exchange Molecular Dynamics.

Shinobu Ai A Re Suyong S Sugita Yuji Y

Frontiers in molecular biosciences 20220429

Molecular dynamics (MD) simulations are increasingly used to study various biological processes such as protein folding, conformational changes, and ligand binding. These processes generally involve slow dynamics that occur on the millisecond or longer timescale, which are difficult to simulate by conventional atomistic MD. Recently, we applied a two-dimensional (2D) replica-exchange MD (REMD) method, which combines the generalized replica exchange with solute tempering (gREST) with the replica- ...[more]

PMID: 35573746

Similar Datasets

Project description:Replica exchange with solute tempering (REST) is a highly effective variant of replica exchange for enhanced sampling in explicit solvent simulations of biomolecules. By scaling the Hamiltonian for a selected "solute" region of the system, REST effectively applies tempering only to the degrees of freedom of interest but not the rest of the system ("solvent"), allowing fewer replicas for covering the same temperature range. A key consideration of REST is how the solute-solvent interactions are scaled together with the solute-solute interactions. Here, we critically evaluate the performance of the latest REST2 protocol for sampling large-scale conformation fluctuations of intrinsically disordered proteins (IDPs). The results show that REST2 promotes artificial protein conformational collapse at high effective temperatures, which seems to be a designed feature originally to promote the sampling of reversible folding of small proteins. The collapse is particularly severe with larger IDPs, leading to replica segregation in the effective temperature space and hindering effective sampling of large-scale conformational changes. We propose that the scaling of the solute-solvent interactions can be treated as free parameters in REST, which can be tuned to control the solute conformational properties (e.g., chain expansion) at different effective temperatures and achieve more effective sampling. To this end, we derive a new REST3 protocol, where the strengths of the solute-solvent van der Waals interactions are recalibrated to reproduce the levels of protein chain expansion at high effective temperatures. The efficiency of REST3 is examined using two IDPs with nontrivial local and long-range structural features, including the p53 N-terminal domain and the kinase inducible transactivation domain of transcription factor CREB. The results suggest that REST3 leads to a much more efficient temperature random walk and improved sampling efficiency, which also further reduces the number of replicas required. Nonetheless, our analysis also reveals significant challenges of relying on tempering alone for sampling large-scale conformational fluctuations of disordered proteins. It is likely that more efficient sampling protocols will require incorporating more sophisticated Hamiltonian replica exchange schemes in addition to tempering.

Dataset Information

Practical Protocols for Efficient Sampling of Kinase-Inhibitor Binding Pathways Using Two-Dimensional Replica-Exchange Molecular Dynamics.

Publications

Practical Protocols for Efficient Sampling of Kinase-Inhibitor Binding Pathways Using Two-Dimensional Replica-Exchange Molecular Dynamics.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets