Date of Award

Fall 1-1-2025

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Chemistry

First Advisor

Batista, Victor

Abstract

This dissertation examines how allosteric communication governs the dual catalytic and immunomodulatory functions of the macrophage migration inhibitory factor (MIF) superfamily, with an emphasis on D-dopachrome tautomerase (MIF-2). Despite limited primary sequence identity, MIF and MIF-2 share a conserved trimeric fold centered on a solvent-accessible channel that connects their catalytic N-terminal proline to distant receptor-binding loops. Experimental work using NMR spin relaxation, site-directed mutagenesis, and in vivo inflammatory assays suggest that single-residue mutations near this channel can dramatically alter tautomerase activity of MIF-2 and its ability to recruit neutrophils in murine lung models, thereby cementing the link between local perturbations and physiological immune responses. To complement these findings, this dissertation also introduces MDiGest, a specialized computational pipeline designed to analyze molecular dynamics simulations to construct residue-residue correlation networks, leveraging multiple descriptors (atomic displacements, torsion angles, electrostatic energies) and advanced metrics (e.g., mutual information and metric difference networks). Through MDiGest analyses, it becomes evident that small disruptions to channel residues recalibrate the entire protein's dynamic landscape, reinforcing that allosteric signals permeate even distant structural elements. This broadens our understanding of how structural changes orchestrate extensive conformational and functional shifts in biologically significant proteins.

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