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NEW YORK – UPSTATE Evaluating The Role for pH-Dependent Histidines to Mediate the Release of the Ebola Virus Fusion Loop Using a Molecular Dynamics Approach

JSHS · 2022

Alex Berkman, Dr. James Munro · Byram Hills High School, Armonk, NY

Overview

Zaire Ebola virus (EBOV) is characterized by potent outbreaks within West Africa and a mortality rate of 50- 90%. Notably, Ebola’s surface glycoprotein, GP, mediates membrane fusion and entry into a cell. GP is dependent on low pH for entry; however, the exact mechanism by which this enables the release of the embedded fusion loop (FL) remains unknown. To uncover the structural changes induced by low pH, two simulations of GP were run. Specifically, histidines in the proximity of the FL (123, 172, 203) were focused on because these amino acids acquire a positive charge under low pH, increasing likelihood of rearrangement needed for fusion. Therefore, in the first simulation, histidines were protonated to model low pH conditions; whereas in the control, histidines remained deprotonated. Next, we utilized a molecular dynamics (MD) tool, Visual MD (VMD), to analyze changes that may enable the release of the FL. A full structural analysis of GP was conducted, in which distances between the two amino acids and the dihedral twist of each residue was calculated. Results showed that low pH destabilizes the domain adjacent to the FL, but has a stabilizing effect on the fusion loop itself. In addition, as predicted, histidines rearrange to interact with residues of opposite charge, as evidenced by enhanced dihedral twist and closer proximity to one another. Ultimately, our study has helped develop a greater mechanistic understanding of the exact conditions required for virus entry, bringing us closer to developing antivirals that exploit this knowledge to fight EBOV infection.

Competition history

  • JSHS 2022 Category not listed

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Source: Junior Science and Humanities Symposium

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