Friday, November 22, 2024
11/22/2024
PROJECT SUMMARY Targeting transient or highly dynamic states of biomolecules with small molecule drugs is a major challenge that must be overcome to advance therapeutic design for human diseases including Alzheimer’s, Parkinson’s, cancer, and viral infections. Studying biomolecules that rapidly change shape or that adopt targetable structures infrequently is a task that is well suited to theoretical investigations in the context of computer-aided drug design. Simulation methods can relate structure to energy, and can provide quantitative descriptions of how small molecules modulate biomolecular structure and dynamics. Our laboratory applies polarizable molecular dynamics (MD) simulations to amyloidogenic proteins and G-quadruplexes (GQs), for which the effects of induced electronic polarization are critical for describing their dynamics. In this application, we propose a research program that seeks to advance drug design efforts against (1) monomeric and membrane-embedded, oligomeric amyloidogenic proteins and (2) G-quadruplexes involved in cancer and viral infections. Throughout these investigations, we focus on the role of induced electronic polarization and electric fields in driving conformational change and ligand binding. We base these efforts on our previous discoveries in how induced polarization influences critical behaviors in these systems and how electric fields exerted within the biomolecules may drive fundamental behaviors. During the project period, we propose to employ cutting-edge strategies for investigating the conformational ensembles of several amyloidogenic peptides in aqueous and phospholipid membranes. We will use structural insights from these simulations to propose new targets for small-molecule design. Similarly, we will investigate structurally diverse GQs in the presence and absence of known ligands to understand the factors driving ligand binding. We will expand upon these efforts with simulations and virtual screening efforts that aim to design new small molecules that will bind GQs with greater specificity than is possible with generic aromatic features. In both of these projects, we will conduct experimental validation of proposed high-affinity compounds using a variety of spectroscopic and biophysical methods. The specific goals for the five-year project period are to (1) determine the conformational free energy landscapes of amyloidogenic proteins and identify dynamic targets and (2) identify substates of GQ ensembles that can be used for high- affinity small-molecule design. These projects reflect the overall vision of the research program, which is to apply the most accurate models and rigorous methods to investigate biomolecular dynamics at the atomic level to understand the molecular basis of disease and to intervene with small-molecule therapeutics.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).
