Multiscale Simulations of Biological Systems and Processes

Project Summary In order to advance the understanding of life processes at the molecular level, we developed multiscale computer simulations that can treat complex biological systems. We intend to apply such strategies to systems which are to important medical problems. Our proposed projects are listed below. A.1 Enzymatic Processes: By exploiting our advances in multiscale modeling, we intend to progress in the following directions: (a) Quantifying computer-aided enzyme design by: (i) reproducing the observed trend in experiments of directed evolution using automatic configuration generator coupled with EVB simulations; (ii) reproducing the catalytic activity of experimentally designed enzymes; (iii) improving the action of promiscuous enzymes; (iv) destroying and rebuilding active sites. Our studies will be done in collaboration with key experimental groups. (b) Continuing to advance the quantitative computational methods, including: (i) using our PD QM(ai)/MM method in for evaluating the ab initio free energy surfaces of enzymatic reactions; (ii) Advancing a maximum entropy approach for fast screening (iii) Quantifying the relationship between folding and catalysis; (c) Conducting studies on important classes of enzymes; (d) Exploring the relations of our findings to medical problems such as the Covid-19 pandemic, drug resistance and other topics like CRISPR. A.2 Multiscale Modeling of the energetics and functions of complex biological systems: Basic functions of living cells are underpinned by proteins that guide the transport of electrons, protons, and ions. Thus, it is crucial to quantitatively explore and exploit the structure-function correlations using computer simulation approaches. We have made a major progress in developing microscopic and coarse grained (CG) approaches for such systems, and we will advance them in the following directions: (a) Simulating the proton transfer (PTR) gating mechanism of cytochrome c oxidase (CcO) and extending our recent studies of FO-ATPase. (b) Exploiting our advances in modeling voltage-gated ion channels for the following purposes: (i) to quantify the interplay between the electrode potential and the protein/membrane energy landscape, (ii) to reproduce the gating voltage and the subsequent ion current and its selectivity using both CG and explicit MC electrolyte models, (iii) to simulating the action of GPCRs and transporters by CG approach, (iv) to explore the relations between our finding and various diseases.