Computational Prediction of Heteromeric Protein Complex Disassembly Order with Hybrid Monte Carlo/Molecular Dynamics Simulation

The physicochemical entity of biological phenomenon in the cell is a network of biochemical reactions and the activity of such a network is regulated by multimeric protein complexes. Mass spectroscopy (MS) experiments and multimeric protein docking simulations based on structural bioinformatics techniques have revealed the molecular-level stoichiometry and static configuration of subcomplexes in their bound forms, then revealing the subcomplex populations and formation orders. Meanwhile, these methodologies are not designed to straightforwardly examine temporal dynamics of multimeric protein assembly and disassembly, essential physicochemical properties to understand functional expression mechanisms of proteins in the biological environment. To address the problem, we had developed an atomistic simulation in the framework of the hybrid Monte Carlo/Molecular Dynamics (hMC/MD) method and succeeded in observing disassembly of homomeric pentamer of the serum amyloid P component protein in experimentally consistent order. In this study, we improved the hMC/MD method to examine disassembly processes of the tryptophan synthase tetramer, a paradigmatic heteromeric protein complex in MS studies. We employed the likelihood-based selection scheme to determine a dissociation-prone subunit pair at each hMC/MD simulation cycle and achieved highly reliable predictions of the disassembly orders with the success rate over 0.9 without a priori knowledge of the MS experiments and structural bioinformatics simulations. We similarly succeeded in reliable predictions for the other three tetrameric protein complexes. These achievements indicate the potential availability of our hMC/MD approach as the general purpose methodology to obtain microscopic and physicochemical insights into multimeric protein complex formation.

Topological sampling through windings

We propose a modification of the Hybrid Monte Carlo (HMC) algorithm that overcomes the topological freezing of a two-dimensional U(1) gauge theory with and without fermion content. This algorithm includes reversible jumps between topological sectors – winding steps – combined with standard HMC steps. The full algorithm is referred to as winding HMC (wHMC), and it shows an improved behaviour of the autocorrelation time towards the continuum limit. We find excellent agreement between the wHMC estimates of the plaquette and topological susceptibility and the analytical predictions in the U(1) pure gauge theory, which are known even at finite $$\beta $$ β . We also study the expectation values in fixed topological sectors using both HMC and wHMC, with and without fermions. Even when topology is frozen in HMC – leading to significant deviations in topological as well as non-topological quantities – the two algorithms agree on the fixed-topology averages. Finally, we briefly compare the wHMC algorithm results to those obtained with master-field simulations of size $$L\sim 8 \times 10^3$$ L ∼ 8 × 10 3 .