# Electrostatic modulation of protein dynamics and interactions > **NIH NIH R01** · UNIVERSITY OF MARYLAND BALTIMORE · 2020 · $347,625 ## Abstract Project Summary/Abstract This renewal proposal seeks to continue the development and application of continuous constant pH molecular dynamics (CpHMD) tools to advance molecular understanding of proteases, kinases and sodium/proton an- tiporters which are involved in Alzheimer's disease, cancer and hypertension, respectively. The objectives of this proposal are to 1) further develop, accelerate and disseminate CpHMD; 2) discover electrostatic modulators of aspartyl proteases and kinases towards selective inhibition; and 3) elucidate the mechanisms of sodium/proton antiporters. Development of a pH stat to properly control solution pH has been a long-standing goal in the MD community. Our recent development of PME-based all-atom CpHMD brought us closer to the goal. In Aim 1, we will add a polarizable force field to take the accuracy of CpHMD to the next level. We will implement CpHMD in other packages to enable alternative implicit-solvent models and force fields. We will implement the code on the GPU platform to allow routine microsecond-scale simulations. The new developments will push the boundary of current MD simulations, transforming pKa calculations and studies of proton-mediated processes. Protonation states and pH effects are a neglected aspect in structure-based drug design due to the lack of tools and understanding. We recently discovered a pH-regulated dynamics-activity relationship for -secretase (a major Alzheimer's drug target) and demonstrated significant pH dependence in small-molecule binding. In Aim 2, we will continue the study of -secretase related aspartyl proteases, and we will tackle challenging questions regarding kinase activation and selective inhibition. Conventional fixed-protonation-state MD with static-structure-based electrostatic calculations cannot reliably iden- tify proton-binding residues and elucidate proton-coupled conformational dynamics. We recently developed the membrane hybrid-solvent CpHMD, which allowed the first constant pH simulations of a proton channel (M2), a sodium/proton antiporter (NhaA) and an efflux pump (AcrB). In Aim 3, we plan to apply this and the new tools developed in Aim 1 to gain further insights into the sodium-proton exchange process in NhaA and to elucidate the distinctive mechanism of another sodium-proton antiporter. These studies will further validate CpHMD and establish it as a powerful tool for studies of proton-coupled transmembrane proteins. In summary, the proposed project will push the boundary of the current predictive power of molecular simulations, transform studies of proton-mediated processes, and generate new insights to accelerate drug discovery targeting Alzheimer's disease, cancer and hypertension. ## Key facts - **NIH application ID:** 9967016 - **Project number:** 5R01GM098818-08 - **Recipient organization:** UNIVERSITY OF MARYLAND BALTIMORE - **Principal Investigator:** Jana Shen - **Activity code:** R01 (R01, R21, SBIR, etc.) - **Funding institute:** NIH - **Fiscal year:** 2020 - **Award amount:** $347,625 - **Award type:** 5 - **Project period:** 2011-09-01 → 2022-02-28 ## Primary source NIH RePORTER: https://reporter.nih.gov/project-details/9967016 ## Citation > US National Institutes of Health, RePORTER application 9967016, Electrostatic modulation of protein dynamics and interactions (5R01GM098818-08). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9967016. Licensed CC0. --- *[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*