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Computational Studies of the Energetics and Dynamics of Protein-Protein Binding

Salari, Reza (2013) Computational Studies of the Energetics and Dynamics of Protein-Protein Binding. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Protein-protein binding is crucial to various processes in living organisms including signal transduction and cell regulation and also plays a central role in various diseases. Therefore, detailed understanding of protein binding is of great importance and is an active area of research in many fields including chemistry, molecular biology and biophysics. In this dissertation, a series of five computational studies were completed to provide molecular details of the energetics and dynamics of model protein-protein complexes.
The first three studies focus on the role of solvent in protein-protein binding. The presence of solvent is very important to the formation of protein-protein complexes through both favorable and unfavorable contributions. For example, the extent to which that salt bridges contribute to the binding stability is predominantly determined by their desolvation penalties, which is difficult to examine experimentally but has been previously studied using implicit solvent models. Here, extensive implicit and explicit solvent simulations were carried out to directly compare the two solvent models in estimating the desolvation penalties of salt bridges upon protein binding. In addition, the effects of high temperature and salt concentration on the desolvation penalties were also explored.
In the fourth study, molecular simulations were employed to model rearrangements of an intermolecular beta sheet in a protein-peptide complex, providing insight into how nature might correct for mistakes in binding orientation for protein-protein interactions involving the formation of beta sheets. The rearrangement mechanism includes a hydrophobic residue of the peptide anchoring itself to a transient hydrophobic pocket on the protein and helping the peptide to “crawl” back to its native state.
Finally, in the fifth study, the relative stabilities of the dimeric and newly discovered trimeric states for a model coiled-coil protein, the GCN4 leucine zipper were compared in isolation. Parallel tempering molecular dynamic simulations in implicit solvent, performed on the microsecond timescale, revealed that while the dimer fold is more stable at room temperature, both oligomers have similar stabilities at temperatures well below the melting temperatures and therefore the same sequence can populate both folds depending on the environment.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Salari, Rezares86@pitt.eduRES86
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairChong, Lillian T.ltchong@pitt.eduLTCHONG
Committee MemberCoalson, Rob D.coalson@pitt.eduCOALSON
Committee MemberHorne, W. Sethhorne@pitt.eduHORNE
Committee MemberZuckerman, Daniel M.ddmmzz@pitt.eduDDMMZZ
Date: 30 January 2013
Date Type: Publication
Defense Date: 13 September 2012
Approval Date: 30 January 2013
Submission Date: 11 September 2012
Access Restriction: 5 year -- Restrict access to University of Pittsburgh for a period of 5 years.
Number of Pages: 180
Institution: University of Pittsburgh
Schools and Programs: Dietrich School of Arts and Sciences > Chemistry
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: protein binding; implicit solvent; explicit solvent; salt bridge; leucine zipper; molecular dynamics; parallel tempering; hyperthermophiles; intermolecular beta-sheet
Date Deposited: 30 Jan 2013 16:31
Last Modified: 30 Jan 2018 06:15

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