Efficient sampling of large-scale transition pathways and intermediate conformations in sub-mesoscopic protein complexes

TL;DR

The paper introduces eBDIMS2, a new algorithm for simulating protein conformational changes in large complexes, enabling efficient exploration of transition pathways.

Contribution

eBDIMS2 is a quasi-linear algorithm for simulating large-scale protein transitions, enabling desktop-level simulation of megadalton complexes.

Findings

eBDIMS2 enables simulation of complex transitions in megadalton protein assemblies like ATP synthases on a desktop.

The algorithm's pathways align with experimental intermediates and enhanced molecular dynamics simulations.

eBDIMS2 integrates elastic networks with Brownian dynamics for sub-mesoscopic systems.

Abstract

Protein conformational changes are the cornerstone of biological function. While conformers captured experimentally represent metastable states, the pathways connecting them have been elusive for experiments and simulations alike. Nowadays, cryogenic Electron Microscopy is providing rich structural data on proteins trapped in different states for increasingly large systems, but these are out of scope for most computational methods which exhibit an N2 dependence on size. Based on our previous eBDIMS algorithm, here we present eBDIMS2, an optimized version with quasi-linear size dependence, able to simulate on a desktop computer particularly complex transitions for megadalton protein assemblies, like the rotary motion of ATP synthases. Not only eBDIMS2 pathways spontaneously visit experimental intermediates but also overlap with enhanced and microsecond Molecular Dynamics simulations requiring extensive supercomputing resources. By integrating Elastic Networks with Brownian Dynamics, eBDIMS2 allows an unprecedented exploration of conformational changes of sub-mesoscopic systems previously inaccessible.

Protein conformational changes underlie many biological functions but remain challenging to model, particularly in large complexes. Here authors introduce eBDIMS2, an improved coarse-grained algorithm for simulating these complex transition pathways in large assemblies

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