ELUCIDATING THE EFFECTS OF MUTATION AND EVOLUTIONARY DIVERGENCE UPON PROTEIN STRUCTURE QUANTITATIVE STABILITY/FLEXIBILITY RELATIONSHIPS

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Verma, D. (2012). ELUCIDATING THE EFFECTS OF MUTATION AND EVOLUTIONARY DIVERGENCE UPON PROTEIN STRUCTURE QUANTITATIVE STABILITY/FLEXIBILITY RELATIONSHIPS. Unc Charlotte Electronic Theses And Dissertations.
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Abstract

The importance of flexibility and stability on protein function has been recognized for over five decades. A protein must be flexible enough to mediate a reaction pathway, yet rigid enough to achieve high fidelity in molecular recognition. To understand these relationships, the main focus of our research has been a comparative investigation of proteins' dynamics and thermodynamics across both "depth" and "breadth". Specifically, we compare stability and flexibility properties across a set of human c-type lysozyme point mutations (depth), as well as across a set of functionally related β-lactamase protein orthologs (breadth). To accomplish these tasks we employ a Distance Constraint Model (DCM), which provides a robust statistical mechanical description of proteins and the relationships therein. The DCM is based on network rigidity that provides mechanical mechanism for enthalpy-entropy compensation, from which Quantitative Stability/Flexibility Relationships (QSFR) can be calculated. Our results suggest that DCM can be used for predicting stability of proteins with an average percent error of 4.3%. Deciphering changes in flexibility, DCM results suggest that the influence of mutations can lead to frequent, large and long-range effects in protein dynamics. Our breadth analyses indicate that QSFR and physiochemical property characterization of orthologs in a protein family parallel evolutionary relationship. Going further, we present protocols for clustering protein structures using their QSFR properties, thus paving way for comprehensive quantitative stability/flexibility relationship analysis across protein families and superfamilies. To summarize, the results presented in this work provide a complete description of proteins that account for their stability, flexibility and function.

Details
Author

Verma, Deeptak

Title

ELUCIDATING THE EFFECTS OF MUTATION AND EVOLUTIONARY DIVERGENCE UPON PROTEIN STRUCTURE QUANTITATIVE STABILITY/FLEXIBILITY RELATIONSHIPS

Physical Description

1 online resource (144 pages) : PDF

Date

2012

Degree Granting Institution

University of North Carolina at Charlotte

Abstract

The importance of flexibility and stability on protein function has been recognized for over five decades. A protein must be flexible enough to mediate a reaction pathway, yet rigid enough to achieve high fidelity in molecular recognition. To understand these relationships, the main focus of our research has been a comparative investigation of proteins' dynamics and thermodynamics across both "depth" and "breadth". Specifically, we compare stability and flexibility properties across a set of human c-type lysozyme point mutations (depth), as well as across a set of functionally related β-lactamase protein orthologs (breadth). To accomplish these tasks we employ a Distance Constraint Model (DCM), which provides a robust statistical mechanical description of proteins and the relationships therein. The DCM is based on network rigidity that provides mechanical mechanism for enthalpy-entropy compensation, from which Quantitative Stability/Flexibility Relationships (QSFR) can be calculated. Our results suggest that DCM can be used for predicting stability of proteins with an average percent error of 4.3%. Deciphering changes in flexibility, DCM results suggest that the influence of mutations can lead to frequent, large and long-range effects in protein dynamics. Our breadth analyses indicate that QSFR and physiochemical property characterization of orthologs in a protein family parallel evolutionary relationship. Going further, we present protocols for clustering protein structures using their QSFR properties, thus paving way for comprehensive quantitative stability/flexibility relationship analysis across protein families and superfamilies. To summarize, the results presented in this work provide a complete description of proteins that account for their stability, flexibility and function.

Genre

doctoral dissertations

Subjects--Topics

Bioinformatics

Degree

Ph.D.

Keywords

Beta-Lactamase
Dynamics
Evolution
Lysozyme
Mutation
Thermodynamics

Subject Area

Information Technology

Advisor(s)

Livesay, Dennis
Jacobs, Donald

Committee Members

Guo, Jun-tao
Krueger, Joanna

Degree Note

Thesis (Ph.D.)--University of North Carolina at Charlotte, 2012.

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Rights Holder Information

Copyright is held by the author unless otherwise indicated.

Identifier

Verma_uncc_0694D_10378

Permalink

http://hdl.handle.net/20.500.13093/etd:1064