Large-Scale Biomolecular Conformational Transitions Explored by a Combined Elastic Network Model and Enhanced Sampling Molecular Dynamics.

Biomolecules often undergo large-scale conformational transitions when carrying out their functions. However, it is still challenging for conventional molecular dynamics simulations to provide adequate structural dynamics information to interpret associated mechanisms. Here, we present a combined elastic network model and enhanced sampling-based strategy (iterANM-IaMD) by adopting iterANM to construct initial conformation space and enhanced sampling IaMD to explore the free energy landscape along specific large-scale conformational transitions. We applied this strategy to three functionally and structurally distinct proteins (adenylate kinase, calmodulin, and p38α kinase), which undergo striking conformational change upon ligand binding. The simulation results for both free and ligand-bound proteins show qualitative and quantitative agreement with existing studies, suggesting iterANM-IaMD as an accurate and efficient tool to investigate structural dynamics involved in complicated biological processes. Our work also provides insights into the relationship between the dynamics and functionality of biomolecules.