Molecular Dynamics Simulation of the Effect of the Crystal Environment on Protein Conformational Dynamics and Functional Motions

Persistent Link:
http://hdl.handle.net/10150/255200
Title:
Molecular Dynamics Simulation of the Effect of the Crystal Environment on Protein Conformational Dynamics and Functional Motions
Author:
Ahlstrom, Logan Sommers
Issue Date:
2012
Publisher:
The University of Arizona.
Rights:
Copyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.
Embargo:
Release after 28-Nov-2013
Abstract:
Proteins are dynamic and interconvert between different conformations to perform their biological functions. Simulation methodology drawing upon principles from classical mechanics - molecular dynamics (MD) simulation - can be used to simulate protein dynamics and reconstruct the conformational ensemble at a level of atomic detail that is inaccessible to experiment. We use the dynamic insight achieved through simulation to enhance our understanding of protein structures solved by X-ray crystallography. Protein X-ray structures provide the most important information for structural biology, yet they depict just a single snapshot of the solution ensemble, which is under the influence of the confined crystal medium. Thus, we ask a fundamental question - how well do static X-ray structures represent the dynamic solution state of a protein? To understand how the crystal environment affects both global and local protein conformational dynamics, we consider two model systems. We first examine the variation in global conformation observed in several solved X-ray structures of the λ Cro dimer by reconstructing the solution ensemble using the replica exchange enhanced sampling method, and show that one X-ray conformation is unstable in solution. Subsequent simulation of Cro in the crystal environment quantitatively assesses the strength of packing interfaces and reveals that mutation in the lattice affects the stability of crystal forms. We also evaluate the Cro models solved by nuclear magnetic resonance spectroscopy and demonstrate that they represent unstable solution states. In addition to our studies of the Cro dimer, we investigate the effect of crystal packing on side-chain conformational dynamics through solution and crystal MD simulation of the HIV microbicide Cyanovirin-N. We find that long, polar surface side-chains can undergo a strong reduction in conformational entropy upon incorporation into crystal contacts, which supports the application of surface engineering to facilitate protein crystallization. Finally, we outline a general framework for using network visualization to aid in the functional interpretation of conformational ensembles generated from MD simulation. Our results will enhance the understanding of X-ray data in establishing protein structure-function-dynamics relationships.
Type:
text; Electronic Dissertation
Keywords:
lambda Cro dimer; molecular dynamics simulation; network visualization; protein X-ray structures; Chemistry; conformational dynamics; crystal packing
Degree Name:
Ph.D.
Degree Level:
doctoral
Degree Program:
Graduate College; Chemistry
Degree Grantor:
University of Arizona
Advisor:
Miyashita, Osamu

Full metadata record

DC FieldValue Language
dc.language.isoenen_US
dc.titleMolecular Dynamics Simulation of the Effect of the Crystal Environment on Protein Conformational Dynamics and Functional Motionsen_US
dc.creatorAhlstrom, Logan Sommersen_US
dc.contributor.authorAhlstrom, Logan Sommersen_US
dc.date.issued2012-
dc.publisherThe University of Arizona.en_US
dc.rightsCopyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.en_US
dc.description.releaseRelease after 28-Nov-2013en_US
dc.description.abstractProteins are dynamic and interconvert between different conformations to perform their biological functions. Simulation methodology drawing upon principles from classical mechanics - molecular dynamics (MD) simulation - can be used to simulate protein dynamics and reconstruct the conformational ensemble at a level of atomic detail that is inaccessible to experiment. We use the dynamic insight achieved through simulation to enhance our understanding of protein structures solved by X-ray crystallography. Protein X-ray structures provide the most important information for structural biology, yet they depict just a single snapshot of the solution ensemble, which is under the influence of the confined crystal medium. Thus, we ask a fundamental question - how well do static X-ray structures represent the dynamic solution state of a protein? To understand how the crystal environment affects both global and local protein conformational dynamics, we consider two model systems. We first examine the variation in global conformation observed in several solved X-ray structures of the λ Cro dimer by reconstructing the solution ensemble using the replica exchange enhanced sampling method, and show that one X-ray conformation is unstable in solution. Subsequent simulation of Cro in the crystal environment quantitatively assesses the strength of packing interfaces and reveals that mutation in the lattice affects the stability of crystal forms. We also evaluate the Cro models solved by nuclear magnetic resonance spectroscopy and demonstrate that they represent unstable solution states. In addition to our studies of the Cro dimer, we investigate the effect of crystal packing on side-chain conformational dynamics through solution and crystal MD simulation of the HIV microbicide Cyanovirin-N. We find that long, polar surface side-chains can undergo a strong reduction in conformational entropy upon incorporation into crystal contacts, which supports the application of surface engineering to facilitate protein crystallization. Finally, we outline a general framework for using network visualization to aid in the functional interpretation of conformational ensembles generated from MD simulation. Our results will enhance the understanding of X-ray data in establishing protein structure-function-dynamics relationships.en_US
dc.typetexten_US
dc.typeElectronic Dissertationen_US
dc.subjectlambda Cro dimeren_US
dc.subjectmolecular dynamics simulationen_US
dc.subjectnetwork visualizationen_US
dc.subjectprotein X-ray structuresen_US
dc.subjectChemistryen_US
dc.subjectconformational dynamicsen_US
dc.subjectcrystal packingen_US
thesis.degree.namePh.D.en_US
thesis.degree.leveldoctoralen_US
thesis.degree.disciplineGraduate Collegeen_US
thesis.degree.disciplineChemistryen_US
thesis.degree.grantorUniversity of Arizonaen_US
dc.contributor.advisorMiyashita, Osamuen_US
dc.contributor.committeememberBrown, Michaelen_US
dc.contributor.committeememberMonti, Oliveren_US
dc.contributor.committeememberSanov, Andreien_US
dc.contributor.committeememberTama, Florenceen_US
dc.contributor.committeememberMiyashita, Osamuen_US
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