09/22/2026
By Michael Brown

The Kennedy College of Sciences, Department of Chemistry, invites you to attend a master’s thesis defense by Kevin Hoover.

  • Date: Tuesday, October 6, 2026
  • Time: 11:30 a.m.
  • Location: Olney Hall, Room 518

Committee

  • Advisor: Matthew Gage, Ph.D., Chemistry Department, University of Massachusetts Lowell
  • Jeffrey Moore, Ph.D., Biology Department, University of Massachusetts Lowell
  • Jin Xu, Ph.D., Chemistry Department, University of Massachusetts Lowell

Brief Abstract

Titin is a giant muscle protein that spans half of the sarcomere and contributes to sarcomere organization, passive elasticity, active force regulation, and mechanosensitive signaling. Within titin, the N2A region functions as a regulatory hub and contains the immunoglobulin-like domains I81, I82, and I83. During intense muscle activity, intracellular pH can decrease to approximately pH 6.5, potentially altering the protonation and stability of these domains. In this study, the effects of acidification on I81, I82, and I83 were examined using urea-induced equilibrium denaturation at pH 6.5, 7.0, and 7.4. Fluorescence center-of-mass measurements were used to determine unfolding free energies, denaturant dependence, and transition midpoints. Residue-specific pKa predictions and fixed-protonation-state molecular dynamics simulations were also used to investigate possible structural mechanisms underlying the experimental trends. The three domains exhibited distinct baseline stabilities and did not respond uniformly to acidification. I82 displayed the clearest acid-associated decrease in transition midpoint, whereas I81 showed a smaller response and I83 remained comparatively insensitive to pH despite having the lowest overall stability. Computational analyses were consistent with I82 having a protonation-sensitive local environment. These results identify I82 as the strongest candidate pH-responsive domain among the isolated N2A immunoglobulin domains and provide a foundation for investigating how fatigue-associated acidification may influence titin structure and mechanics.