Advances and Applications in Bioinformatics and Chemistry (Jan 2022)
Binding Analysis Using Accelerated Molecular Dynamics Simulations and Future Perspectives
Abstract
Shristi Pawnikar, Apurba Bhattarai, Jinan Wang, Yinglong Miao Center for Computational Biology and Department of Molecular Biosciences, University of Kansas, Lawrence, KS, 66047, USACorrespondence: Yinglong MiaoCenter for Computational Biology, University of Kansas, 2030 Becker Drive, Room 200D MRB, Lawrence, KS, 66047, USAEmail [email protected]: Biomolecular recognition such as binding of small molecules, nucleic acids, peptides and proteins to their target receptors plays key roles in cellular function and has been targeted for therapeutic drug design. Molecular dynamics (MD) is a computational approach to analyze these binding processes at an atomistic level, which provides valuable understandings of the mechanisms of biomolecular recognition. However, the rather slow biomolecular binding events often present challenges for conventional MD (cMD), due to limited simulation timescales (typically over hundreds of nanoseconds to tens of microseconds). In this regard, enhanced sampling methods, particularly accelerated MD (aMD), have proven useful to bridge the gap and enable all-atom simulations of biomolecular binding events. Here, we will review the recent method developments of Gaussian aMD (GaMD), ligand GaMD (LiGaMD) and peptide GaMD (Pep-GaMD), which have greatly expanded our capabilities to simulate biomolecular binding processes. Spontaneous binding of various biomolecules to their receptors has been successfully simulated by GaMD. Microsecond LiGaMD and Pep-GaMD simulations have captured repetitive binding and dissociation of small-molecule ligands and highly flexible peptides, and thus enabled ligand/peptide binding thermodynamics and kinetics calculations. We will also present relevant application studies in simulations of important drug targets and future perspectives for rational computer-aided drug design.Keywords: biomolecular recognition, accelerated molecular dynamics, thermodynamics, kinetics, drug design
