# Design and application of robust and efficient QM/MM free energy simulation methods for biomolecular systems

> **NIH NIH R01** · UNIVERSITY OF SOUTH FLORIDA · 2020 · $284,873

## Abstract

Project Summary / Abstract
To accurately compute free energies of complex biomolecular systems there are two key prerequisites: the accurate
description of inter- and intramolecular interactions, and adequate sampling of all relevant conformational degrees of
freedom. Include the possibility that conformational dynamics may be coupled to complex electronic processes or
chemical reactions, where quantum mechanical (QM) methods are needed, and this task becomes extremely daunt-
ing. Currently, whenever accurate computations of biomolecular systems are essential, the tool of choice is hybrid
quantum mechanical / molecular mechanical (QM/MM) calculations, however, the application of these techniques to
free energy simulations (FES) is far from common. Herein, we aim to develop a set of robust, efficient, and accurate
new techniques that will make the application of QM/MM FES nearly routine. These methods will be subsequently ap-
plied to study two classes of biomolecular applications that present extreme challenges to current techniques. Namely,
the accurate computation of (1) absolute pKa as a function of ligand binding and reaction (e.g., accounting for tran-
sient interactions), and (2) free energy differences of binding as a function of tautomerism. The scientific results will
be closely tied to activities aimed at improving access to these advanced techniques.

## Key facts

- **NIH application ID:** 10004158
- **Project number:** 5R01GM129519-03
- **Recipient organization:** UNIVERSITY OF SOUTH FLORIDA
- **Principal Investigator:** Henry Lee Woodcock III
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $284,873
- **Award type:** 5
- **Project period:** 2018-09-01 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10004158

## Citation

> US National Institutes of Health, RePORTER application 10004158, Design and application of robust and efficient QM/MM free energy simulation methods for biomolecular systems (5R01GM129519-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10004158. Licensed CC0.

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