Reaction Pathway Sampling and Free Energy Analyses for Multimeric Protein Complex Disassembly with Employing Hybrid Configuration Bias Monte Carlo/Molecular Dynamics Simulation

Abstract

Physicochemical characterization of multimeric biomacromolecule assembly and disassembly processes is a milestone to understand the mechanisms for biological phenomena at molecular level. Mass spectroscopy (MS) and structural bioinformatics (SB) approaches have become feasible to identify subcomplexes involved in assembly and disassembly, while they cannot provide atomic information sufficient for free energy calculation to characterize transition mechanism between two different sets of subcomplexes. To combine observations derived from MS and SB approaches with conventional free energy calculation protocols, we here designed a new reaction pathway sampling method with employing hybrid configuration bias Monte Carlo/Molecular Dynamics (hcbMC/MD) scheme and applied it to simulate disassembly process of serum amyloid P component (SAP) pentamer. The results we obtained are consistent with those of the earlier MS and SB studies with respect to SAP subcomplex species and the initial stage of SAP disassembly processes. Furthermore, we observed a novel dissociation event, ring-opening reaction of SAP pentamer. Employing free energy calculation combined with the hcbMC/MD reaction pathway trajectories, we moreover obtained experimentally testable observations on (1) reaction time of the ring-opening reaction and (2) importance of Asp42 and Lys117 for stable formation of SAP oligomer.TOC graphics

Non-micelle-like Amyloid Aggregate Stabilizes Amyloid β (1-42) Growth Nuclei Formation

“…The 40 monomers, which are the part of Aβ 42 (25:25), are dissociated to prepare amyloid aggregate milieu by repetitive steered MD simulations. The sequential dissociations of monomers were carried out in the framework of hybrid MC/MD method, which we employed to study disassembly processes of the homomeric protein multimer 22 .…”

“…We start from testing the speculation, which we made in the previous study 21 : an Aβ 42 aggregate crowding milieu suppresses Aβ 42 monomer dissociations from a growth edge of Aβ 42 growth nuclei and prevents disassembly of the growth nuclei. To overcome the above experimental difficulty, we theoretically modeled the atomic configuration of Aβ 42 aggregate milieu by employing the hybrid Monte Carlo/Molecular Dynamics (MC/MD) approach, which we had developed to examine dynamic processes of multimeric proteins 22,23 . By using the simulation-derived Aβ 42 aggregate milieu systems for the free energy calculation of Aβ 42 monomer dissociation from the protomer dimer, we confirmed the stabilization effect of Aβ 42 aggregate milieus on Aβ 42 growth nuclei formation via Aβ 42 suppressing monomer dissociation from the growth edge.…”