Program: Computational and Systems Biology
Current advisor: Gregory R. Bowman, PhD
Undergraduate university: Harvard University
Mutations in myosin motors cause a number of debilitating diseases, including hypertrophic cardiomyopathy, the leading cause of sudden cardiac death in patients under 35. Despite the prevalence of hypertrophic cardiomyopathy, the precise mechanism by which mutations in beta-cardiac myosin (MYH7) give rise to cardiomyopathy remains unknown, and many myosin mutations fall into the category of “variants of unknown significance”. Therefore, interpreting variants in the MYH7 gene and developing new treatments specific to an individual patient’s beta-cardiac myosin is of great clinical interest. A recent publication by Porter, Meller, et al. comparing the conformational ensembles of isolated myosin motor domains reveals signatures that correspond to biochemical differences in thermodynamics and nucleotide handling kinetics. To extend this work into the clinical realm, I analyze the conformational ensembles of cardiomyopathy mutants in both isolated myosin motors and a two-myosin structure believed to represent a relaxed state whose stability may be reduced by hypertrophic cardiomyopathy mutations. Then, using our detailed understanding of conformational differences across different myosin motor domains and cardiomyopathy mutants, I will predict the biochemical properties of mutants that have not been experimentally characterized and the pathogenicity of variants of unknown significance.
Ward MD, Zimmerman MI, Meller A, Chung M, Swamidass SJ, Bowman GR. 2021 Deep learning the structural determinants of protein biochemical properties by comparing structural ensembles with DiffNets. Nat Commun, 12(1):3023.
Zimmerman MI, Porter JR, Ward MD, Singh S, Vithani N, Meller A, Mallimadugula UL, Kuhn CE, Borowsky JH, Wiewiora RP, Hurley MFD, Harbison AM, Fogarty CA, Coffland JE, Fadda E, Voelz VA, Chodera JD, Bowman GR. 2021 SARS-CoV-2 simulations go exascale to predict dramatic spike opening and cryptic pockets across the proteome. Nat Chem, 13(7):651-59.
Porter JR, Meller A, Zimmerman MI, Greenberg MJ, Bowman GR. 2020 Conformational distributions of isolated myosin motor domains encode their mechanochemical properties. Elife, 9():e55132.