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

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.

Ligand-mediated Structural Dynamics of a Mammalian Pancreatic K Channel.

Regulation of pancreatic K channels involves orchestrated interactions of their subunits, Kir6.2 and SUR1, and ligands. Previously we reported K channel cryo-EM structures in the presence and absence of pharmacological inhibitors and ATP, focusing on the mechanisms by which inhibitors act as pharmacological chaperones of K channels (Martin et al.

A gentle introduction to the non-equilibrium physics of trajectories: Theory, algorithms, and biomolecular applications.

Despite the importance of non-equilibrium statistical mechanics in modern physics and related fields, the topic is often omitted from undergraduate and core-graduate curricula. Key aspects of non-equilibrium physics, however, can be understood with a minimum of formalism based on a rigorous trajectory picture. The fundamental object is the ensemble of trajectories, a set of independent time-evolving systems, which easily can be visualized or simulated (e.

WESTPA 2.0: High-Performance Upgrades for Weighted Ensemble Simulations and Analysis of Longer-Timescale Applications.

The weighted ensemble (WE) family of methods is one of several statistical mechanics-based path sampling strategies that can provide estimates of key observables (rate constants and pathways) using a fraction of the time required by direct simulation methods such as molecular dynamics or discrete-state stochastic algorithms. WE methods oversee numerous parallel trajectories using intermittent overhead operations at fixed time intervals, enabling facile interoperability with any dynamics engine. Here, we report on the major upgrades to the WESTPA software package, an open-source, high-performance framework that implements both basic and recently developed WE methods.

Vascular K channel structural dynamics reveal regulatory mechanism by Mg-nucleotides.

Vascular tone is dependent on smooth muscle K channels comprising pore-forming Kir6.1 and regulatory SUR2B subunits, in which mutations cause Cantú syndrome. Unique among K isoforms, they lack spontaneous activity and require Mg-nucleotides for activation.