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Computational investigations of cellular functions: Three cases on membrane morphogenesis, organization and assembly of a multi-protein complex, and the molecular origin of muscle elasticity

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Title: Computational investigations of cellular functions: Three cases on membrane morphogenesis, organization and assembly of a multi-protein complex, and the molecular origin of muscle elasticity
Author(s): Hsin, Ya-chieh
Director of Research: Schulten, Klaus J.
Doctoral Committee Chair(s): Aksimentiev, Aleksei
Doctoral Committee Member(s): Ha, Taekjip; Hubler, Alfred W.; Schulten, Klaus J.
Department / Program: Physics
Discipline: Physics
Degree Granting Institution: University of Illinois at Urbana-Champaign
Degree: Ph.D.
Genre: Dissertation
Subject(s): molecular dynamics steered molecular dynamics photosynthesis membrane curvature protein-induced membrane curvature molecular modeling protein complex assembly muscle elasticity titin mechanical protein elastic protein
Abstract: In this article, three biological inquiries on cellular functions investigated through a combination of theoretical and computational methods are discussed: the morphology of the biological membrane, assembly of a multi-protein complex, and the molecular origin of elasticity in muscle protein. In the photosynthetic purple bacterium Rhodobacter (Rba.) sphaeroides, light is absorbed by membrane-bound light-harvesting proteins LH1 and LH2. LH1 directly surrounds the reaction center (RC) and, together with PufX, forms a dimeric (RC-LH1-PufX)2 protein complex known as the photosynthetic core complex. In LH2-deficient Rba . sphaeroides mutants, core complex dimers aggregate into tubular vesicles with a radius of ∼25-55 nm, making core complex dimer one of the few integral membrane proteins known to actively induce membrane curvature. A three-dimensional electron microscopy density map showed that the Rba . sphaeroides core complex dimer exhibits a prominent bend at its dimerizing interface. To investigate the curvature properties of this highly bent protein, molecular dynamics simulations were employed to fit an all-atom structural model of the core complex dimer within the electron microscopy density map. The simulations reveal how the dimer produces a membrane with high local curvature, the curvature matching the size of the tubular vesicles containing only core complex dimers. To understand the molecular basis of the bent geometry of the Rba . sphaeroides core complex dimer, the PufX protein was subject to further investigation. To date, no high resolution structure is available for the entire Rba. sphaeroides core complex dimer. In particular, the location of PufX within the core complex dimer is debated. Placement of PufX has direct implication on the dimerizing mechanism and the self-assembly process of the Rba. sphaeroides core complex dimer. We have constructed and tested via molecular dynamics a model of PufX dimer based on the Glycophorin A (GlyA) dimer. The PufX dimer model was shown to be structurally stable both in its monomeric and dimeric states, and the residues participating in PufX helix-helix interactions in the dimeric state were identified. The dimerized PufX helices display a stable GlyA-like crossing angle, which, during the self-assembly process, possibly results in the highly bent and V-shaped structure of core complex dimer responsible for inducing local membrane curvature in the photosynthetic membrane. Titin is a mechanical protein that protects muscle from overstretching by producing a restoring force when a muscle fiber is extended beyond its normal length. Force spectroscopy studies have shown that titin exhibits several regimes of elasticity. Disordered segments bring about a soft, entropic spring-type elasticity; secondary structures of titins immunoglobulin-like (Ig-) and fibronectin type III-like (FN-III) domains provide a stiff elasticity. We demonstrated that titin exhibits a third type of elasticity due to tertiary structure and involving domain-domain interaction and reorganization along the titin chain. Through simulations employing equilibrium molecular dynamics, steered molecular dynamics, and free-energy calculations, the mechanical properties of a six-Ig domain of titin (I65-I70), for which a crystallographic structure is available, were investigated. The results reveal a soft tertiary structure elasticity. A remarkably accurate statistical mechanical description for this elasticity is derived and applied. Simulations studied also the stiff, secondary structure elasticity of the I65-I70 chain due to the unraveling of its domains and revealed how force propagates along the chain during the secondary structure elasticity response.
Issue Date: 2010-08-20
URI: http://hdl.handle.net/2142/16835
Rights Information: Copyright 2010 Ya-chieh Hsin
Date Available in IDEALS: 2010-08-20
Date Deposited: 2010-08
 

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