Adaptive Ensemble Refinement of Protein Structures in High Resolution Electron Microscopy Density Maps with Radical Augmented Molecular Dynamics Flexible Fitting

Abstract

Recent advances in cryo-electron microscopy (cryo-EM) has enabled modeling macromolecular complexes that are essential components of life. The density maps obtained from cryo-EM experiments is often integrated with ab-initio, knowledge-driven or first principles-based computational methods to build, fit and refine protein structures inside the electron density maps. Going beyond a single stationary-structure determination scheme, it is becoming more common to interpret the experimental data with a set of multiple physical models all of which contributes to the average observation seen by the experiment. Hence, there is a need to decide on the quality of an ensemble of protein structures on-the-fly, while refining them against the density maps. In this work, we demonstrate such adaptive decision making capabilities during flexible fitting of biomolecules. Our solution uses RADICAL tools (RCT) and we test this new implementation in exascale high performance computing environment for two proteins, Adenylate Kinase (ADK) and Carbon Monoxide Dehydrogenase (CODH). Our results indicate that using multiple replicas in flexible fitting with adaptive decision making improves the overall quality of fit and model by 40 % improvement when compared against the traditional flexible fitting approach. These advances are agnostic to system-size and computing environments.

MDFF_NM: Improved Molecular Dynamics Flexible Fitting into Cryo-EM Density Maps with a Multireplica Normal Mode-Based Search

“…The latter is an ensemble-based flexible fitting tool that also demonstrated encouraging results. 39 Once again, given that both MDFF_NM and R-MDFF are replica-based tools, incorporating NM-driven sampling into the latter would not disrupt the inherent nature of the method.…”

LongBondEliminator: A Molecular Simulation Tool to Remove Ring Penetrations in Biomolecular Simulation Systems

“…CHARMM-GUI [26,27] and Membrane Mixer [25] take advantage of fast insertion of lipid or sterol into bilayers to either let dynamics reinsert a molecule after pulling it out or carve a space using density grids before adding a lipid in the first place. Alternatively, it may be possible to use robotic motion planning algorithms [53] or molecular dynamics with adaptive decision making [54] to engineer realistic molecular geometries for complex systems without the expensive minimization and reminimization steps.…”

Comparative Pore Structure and Dynamics for Bacterial Microcompartment Shell Protein Assemblies in Sheets or Shells

“…To create a planar sheet-like structure, we use molecular dynamics flexible fitting (MDFF) 24,24,25 to flatten the initial structure (Fig. 2).…”