Living Journal of Computational Molecular Science

A Suite of Tutorials for the WESTPA 2.0 Rare-Events Sampling Software [Article v2.0]

Anthony T. Bogetti — 2023-04-10

The weighted ensemble (WE) strategy has been demonstrated to be highly efficient in generating pathways and rate constants for rare events such as protein folding and protein binding using atomistic molecular dynamics simulations. Here we present two sets of tutorials instructing users in the best practices for preparing, carrying out, and analyzing WE simulations for various applications using the WESTPA software. The first set of more basic tutorials describes a range of simulation types, from a molecular association process in explicit solvent to more complex processes such as host-guest association, peptide conformational sampling, and protein folding. The second set ecompasses six advanced tutorials instructing users in the best practices of using key new features and plugins/extensions of the WESTPA 2.0 software package, which consists of major upgrades for larger systems and/or slower processes. The advanced tutorials demonstrate the use of the following key features: (i) a generalized resampler module for the creation of “binless” schemes, (ii) a minimal adaptive binning scheme for more efficient surmounting of free energy barriers, (iii) streamlined handling of large simulation datasets using an HDF5 framework, (iv) two different schemes for more efficient rate-constant estimation, (v) a Python API for simplified analysis of WE simulations, and (vi) plugins/extensions for Markovian Weighted Ensemble Milestoning and WE rule-based modeling for systems biology models. Applications of the advanced tutorials include atomistic and non-spatial models, and consist of complex processes such as protein folding and the membrane permeability of a drug-like molecule. Users are expected to already have significant experience with running conventional molecular dynamics or systems biology simulations.

A Suite of Tutorials for the BioSimSpace Framework for Interoperable Biomolecular Simulation [Article v1.0]

Lester O. Hedges — 2023-12-16

This tutorial serves as a getting-started guide for BioSimSpace (BSS), an interoperable molecular simulation framework, that allows simulations with different sets of molecular dynamics software packages. This tutorial will cover four main use cases for BioSimSpace. The introductory tutorial introduces the basic structure of BioSimSpace, how to use the API to access functionality, and how to write code for setting up and running standard molecular dynamics simulations. Three advanced use cases of BSS are then provided, describing how to set up and run a funnel metady- namics simulation, steered molecular dynamics, and relative or absolute alchemical binding free energy calculations.

Computing Absolute Binding Affinities by Streamlined Alchemical Free Energy Perturbation (SAFEP) [Article v1.0]

Ezry Santiago-McRae — 2023-10-23

Free Energy Perturbation (FEP) is a powerful but challenging computational technique for estimating differences in free energy between two or more states. This document is intended both as a tutorial and as an adaptable protocol for computing free energies of binding using free energy perturbations in NAMD. We present the Streamlined Alchemical Free Energy Perturbation (SAFEP) framework. SAFEP shifts the computational frame of reference from the ligand to the binding site itself. This both simplifies the thermodynamic cycle and makes the approach more broadly applicable to superficial sites and other less common geometries. As a practical example, we give instructions for calculating the absolute binding free energy of phenol to lysozyme. We assume familiarity with standard procedures for setting up, running, and analyzing molecular dynamics simulations using NAMD and VMD. While simulation times will vary, the human tasks should take no more than 3 to 4 hours for a reader without previous training in free energy calculations or ex- perience with the VMD Colvars Dashboard. Sample data are provided for all key calculations both for comparison and readers’ convenience.

An Introductory Tutorial to the SEEKR2 (Simulation Enabled Estimation of Kinetic Rates v. 2) Multiscale Milestoning Software [Article v1.0]

Anupam Anand Ojha — 2024-02-16

SEEKR2 (Simulation enabled estimation of kinetic rates v. 2) is a powerful and versatile software tool designed to computationally estimate the kinetics and thermodynamics of complex molecular processes, particularly emphasizing the process of receptor-ligand binding and unbinding. We present a suite of tutorials for the SEEKR2 (Simulation enabled estimation of kinetic rates v. 2) multiscale milestoning software. This tutorial presents a comprehensive guide for users offering the best practices for preparing, executing, and analyzing molecular dynamics (MD) and Brownian dynamics (BD) simulations using SEEKR2. This tutorial highlights the advancements presented in SEEKR2 - the latest iteration within the SEEKR programs, including significant improvements in speed and capabilities compared to its earlier versions. SEEKR2 now supports both NAMD and OpenMM simulation engines, providing users with more flexibility in their simulation setups. Additionally, the BD component has been upgraded to the Browndye2 engine, enhancing the accuracy and efficiency of simulations. This tutorial aims to guide users to install SEEKR2, run MD and BD simulations within the framework of the SEEKR2 program, and analyze and interpret the kinetics and thermodynamics of binding and unbinding of model host-guest systems, thereby demonstrating its ease of usability and extensible features that allow for future expansions of the method. This tutorial equips users with the necessary knowledge to effectively prepare, execute, and analyze simulations using SEEKR2. By following the best practices outlined in the tutorial, users can leverage the power of the SEEKR2 program to gain insights into complex molecular processes and accelerate their understanding of key biomolecular interactions.