Simulations of Functional Motions of Super Large Biomolecules with a Mixed-Resolution Model

• Published in: Journal of chemical theory and computation Vol. 20; no. 5; pp. 2228 - 2245
• Main Authors: Li, Shu, Wu, Bohua, Luo, Yun Lyna, Han, Wei
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 12.03.2024
• Subjects: Biomolecular Systems; Biomolecules; Interaction parameters; Ion channels; Mathematical models; Membranes; Proteins; Rescaling; Scaling factors; Structural stability
• ISSN: 1549-9618; 1549-9626
• DOI: 10.1021/acs.jctc.3c01046

Many large protein machines function through an interplay between large-scale movements and intricate conformational changes. Understanding functional motions of these proteins through simulations becomes challenging for both all-atom and coarse-grained (CG) modeling techniques because neither approach alone can readily capture the full details of these motions. In this study, we develop a multiscale model by employing the popular MARTINI CG model to represent a heterogeneous environment and structurally stable proteins and using the united-atom (UA) model PACE to describe proteins undergoing subtle conformational changes. PACE was previously developed to be compatible with the MARTINI solvent and membrane. Here, we couple the protein descriptions of the two models by directly mixing UA and CG interaction parameters to greatly simplify parameter determination. Through extensive validations with diverse protein systems in solution or membrane, we demonstrate that only additional parameter rescaling is needed to enable the resulting model to recover the stability of native structures of proteins under mixed representation. Moreover, we identify the optimal scaling factors that can be applied to various protein systems, rendering the model potentially transferable. To further demonstrate its applicability for realistic systems, we apply the model to a mechanosensitive ion channel Piezo1 that has peripheral arms for sensing membrane tension and a central pore for ion conductance. The model can reproduce the coupling between Piezo1’s large-scale arm movement and subtle pore opening in response to membrane stress while consuming much less computational costs than all-atom models. Therefore, our model shows promise for studying functional motions of large protein machines.