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Ensemble Interpretation of Domain Mobility in Modular Protein Pin1 by NMR and Molecular Dynamics

thesis
posted on 2014-12-08, 00:00 authored by Jill J Bouchard
The majority of proteins have multiple independently folding and functioning domains; this is known as protein modularity. Most of these molecular machines are tethered together by flexible linkers. Consequently, there is a lot of mobility between the domains of modular proteins. This mobility allows proteins to use interdomain motion to carry out their functions, often with different partners. Thus, if we want to understand how modular proteins function, we must characterize the range of conformations modular proteins sample. This thesis makes strides to describe the biophysical behavior of modular proteins and understand how their interdomain motions matter for function. The result is new developments in molecular biophysics on two levels; (i) methodological and (ii) biological. A biophysical method to describe flexible systems needs to be dynamic, or at least, characterize the ensemble of conformations visited. This thesis demonstrates a new way to do this. We recognized the power of combining NMR parameters that can resolve long-range atomic information with molecular dynamics to view the atomic details of these large-scale motions. To this end, we developed the MapSGLD-NMR method for quantitatively describing interdomain orientations of modular proteins. As a test system for this new method, this thesis focuses on human Pin1, a two-domain signaling protein of therapeutic relevance because it is implicated in Alzheimer?s disease, cancer, and many other human diseases. The ensemble description of Pin1 uncovers insights about its interaction modes with different binding partners. The results suggest we can control interdomain motions of Pin1. The biological impact of this work is that we may be able to account for interdomain motions to improve drug discovery tactics for modular proteins.

History

Date Created

2014-12-08

Date Modified

2019-03-11

Defense Date

2014-11-24

Research Director(s)

Jeffrey W. Peng

Committee Members

Patricia L. Clark Zachary Schultz

Degree

  • Doctor of Philosophy

Degree Level

  • Doctoral Dissertation

Language

  • English

Alternate Identifier

etd-12082014-000142

Publisher

University of Notre Dame

Program Name

  • Chemistry and Biochemistry

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