# A Systematic Toolkit for Counteracting HIV Drug Resistance with Protein Structural Dynamics

> **NIH NIH R21** · UNIVERSITY OF ILLINOIS AT CHICAGO · 2024 · $176,096

## Abstract

Project Summary
HIV-1 presents a severe global health challenge. Due to the high genetic variability of HIV and the lifelong
duration of the standard treatment, resistant mutations pose an acute challenge. As such, understanding the
mechanisms of resistance is crucial for the rational design of antivirals. The current approach for
understanding drug resistance focuses on identifying important interactions in the protein-drug complex based
on intuitions. These insights have led to intriguing structure-based drug design strategies. However,
resistance for drugs designed by these strategies readily developed, reflecting their limitations. This is due to
two major gaps in the current approach: (1) It does not consider the conformational dynamics inherent to
ligand binding, which are vital to decoding drug resistance. For example, the interplay between active-site
and non-active site mutations in PR cannot be understood from structures alone. (2) This empirical, qualitative
approach lacks a rigorous method to quantify how different residues and interactions individually and
collectively contribute to binding affinity. We propose to fill these two gaps with a physics-based rigorous
approach centered on protein conformational dynamics that control ligand binding, the process at the heart
of drug potency and resistance. We will leverage a novel method we developed for identifying the exact
reaction coordinates, the few essential coordinates of a protein that control its conformational dynamics and
ligand binding. We will develop a rigorous method for decomposing the ligand binding free energy into
contributions from individual residue-residue interactions. This method will enable us to identify residues and
interactions critical for drug resistance. We will apply it to HIV-1 protease inhibitors, aiming to elucidate the
mechanisms of resistance. We will also develop protocols for adjusting protein-protein and protein-ligand
interactions to manipulate protein dynamics and combat drug resistance. To verify our understanding of
resistance mechanisms and protocols for manipulating protein interactions and dynamics, we will test two
types of computational predictions in infection assays. 1) We will design mutations that confer stronger
resistance than current variants, aiming to establish the limits of drug resistance. 2) We will introduce
additional mutations to existing mutants to neutralize their resistance, aiming to establishing the range for
countering resistance. These will be achieved through two specific aims. The goal of this project is to develop
a computational toolkit for rigorously and systematically dissecting protein drug resistance mechanisms that
will enable rationale design of effective counterstrategies and validate it with virology assays. The insights
from this project will fuel our long-term goal: to design the next-generation HIV antivirals that not only
neutralize current resistant mutants but also minimize chances of new resistant mut...

## Key facts

- **NIH application ID:** 11013504
- **Project number:** 1R21AI186936-01
- **Recipient organization:** UNIVERSITY OF ILLINOIS AT CHICAGO
- **Principal Investigator:** Ao Ma
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $176,096
- **Award type:** 1
- **Project period:** 2024-08-01 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11013504

## Citation

> US National Institutes of Health, RePORTER application 11013504, A Systematic Toolkit for Counteracting HIV Drug Resistance with Protein Structural Dynamics (1R21AI186936-01). Retrieved via AI Analytics 2026-06-03 from https://api.ai-analytics.org/grant/nih/11013504. Licensed CC0.

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