An exa-scale high-performance molecular dynamics simulation program: MODYLAS.

A new version of the highly parallelized general-purpose molecular dynamics (MD) simulation program MODYLAS with high performance on the Fugaku computer was developed. A benchmark test using Fugaku indicated highly efficient communication, single instruction, multiple data (SIMD) processing, and on-cache arithmetic operations. The system's performance deteriorated only slightly, even under high parallelization.

Binding Kinetics Toolkit for Analyzing Transient Molecular Conformations and Computing Free Energy Landscapes.

Understanding ligand binding kinetics and thermodynamics, which involves investigating the free, transient, and final complex conformations, is important in fundamental studies and applications for chemical and biomedical systems. Examining the important but transient ligand-protein-bound conformations, in addition to experimentally determined structures, also provides a more accurate estimation for drug efficacy and selectivity. Moreover, obtaining the entire picture of the free energy landscape during ligand binding/unbinding processes is critical in understanding binding mechanisms.

Transient States and Barriers from Molecular Simulations and the Milestoning Theory: Kinetics in Ligand-Protein Recognition and Compound Design.

This study presents a novel computational approach to study molecular recognition and binding kinetics for drug-like compounds dissociating from a flexible protein system. The intermediates and their free energy profile during ligand association and dissociation processes control ligand-protein binding kinetics and bring a more complete picture of ligand-protein binding. The method applied the milestoning theory to extract kinetics and thermodynamics information from running short classical molecular dynamics (MD) simulations for frames from a given dissociation path.

Potential Mean Force from Umbrella Sampling Simulations: What Can We Learn and What Is Missed?

Changes in free energy provide valuable information for molecular recognition, including both ligand-receptor binding thermodynamics and kinetics. Umbrella sampling (US), a widely used free energy calculation method, has long been used to explore the dissociation process of ligand-receptor systems and compute binding free energy. In existing publications, the binding free energy computed from the potential of mean force (PMF) with US simulation mostly yielded "ball park" values with experimental data.

An MM and QM Study of Biomimetic Catalysis of Diels-Alder Reactions Using Cyclodextrins.

We performed a computational investigation of the mechanism by which cyclodextrins (CDs) catalyze Diels-Alder reactions between 9-anthracenemethanol and -cyclohexylmaleimide. Hydrogen bonds (Hbonds) between -cyclohexylmaleimide and the hydroxyl groups of cyclodextrins were suggested to play an important role in this catalytic process. However, our free energy calculations and molecular dynamics simulations showed that these Hbonds are not stable, and quantum mechanical calculations suggested that the reaction is not promoted by these Hbonds.

A molecular dynamics investigation of CDK8/CycC and ligand binding: conformational flexibility and implication in drug discovery.

Abnormal activity of cyclin-dependent kinase 8 (CDK8) along with its partner protein cyclin C (CycC) is a common feature of many diseases including colorectal cancer. Using molecular dynamics (MD) simulations, this study determined the dynamics of the CDK8-CycC system and we obtained detailed breakdowns of binding energy contributions for four type-I and five type-II CDK8 inhibitors. We revealed system motions and conformational changes that will affect ligand binding, confirmed the essentialness of CycC for inclusion in future computational studies, and provide guidance in development of CDK8 binders.

Binding Thermodynamics and Kinetics Calculations Using Chemical Host and Guest: A Comprehensive Picture of Molecular Recognition.

Understanding the fine balance between changes of entropy and enthalpy and the competition between a guest and water molecules in molecular binding is crucial in fundamental studies and practical applications. Experiments provide measurements. However, illustrating the binding/unbinding processes gives a complete picture of molecular recognition not directly available from experiments, and computational methods bridge the gaps.

Systematic Dissociation Pathway Searches Guided by Principal Component Modes.

We introduce a novel method, Pathway Search guided by Internal Motions (PSIM), that efficiently finds molecular dissociation pathways of a ligand-receptor system with guidance from principal component (PC) modes obtained from molecular dynamics (MD) simulations. Modeling ligand-receptor dissociation pathways can provide insights into molecular recognition and has practical applications, including understanding kinetic mechanisms and barriers to binding/unbinding as well as design of drugs with desired kinetic properties. PSIM uses PC modes in multilayer internal coordinates to identify natural molecular motions that guide the search for conformational switches and unbinding pathways.

Adaptation of a Genetic Screen Reveals an Inhibitor for Mitochondrial Protein Import Component Tim44.

Diverse protein import pathways into mitochondria use translocons on the outer membrane (TOM) and inner membrane (TIM). We adapted a genetic screen, based on Ura3 mistargeting from mitochondria to the cytosol, to identify small molecules that attenuated protein import. Small molecule mitochondrial import blockers of the Carla Koehler laboratory (MB)-10 inhibited import of substrates that require the TIM23 translocon.

Understanding ligand-receptor non-covalent binding kinetics using molecular modeling.

Kinetic properties may serve as critical differentiators and predictors of drug efficacy and safety, in addition to the traditionally focused binding affinity. However the quantitative structure-kinetics relationship (QSKR) for modeling and ligand design is still poorly understood. This review provides an introduction to the kinetics of drug binding from a fundamental chemistry perspective.