# Multiscale Simulations of Biological Systems and Processes

> **NIH NIH R35** · UNIVERSITY OF SOUTHERN CALIFORNIA · 2024 · $620,400

## Abstract

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.

## Key facts

- **NIH application ID:** 10927353
- **Project number:** 5R35GM122472-08
- **Recipient organization:** UNIVERSITY OF SOUTHERN CALIFORNIA
- **Principal Investigator:** ARIEH WARSHEL
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $620,400
- **Award type:** 5
- **Project period:** 2017-05-01 → 2027-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10927353

## Citation

> US National Institutes of Health, RePORTER application 10927353, Multiscale Simulations of Biological Systems and Processes (5R35GM122472-08). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10927353. Licensed CC0.

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