Bulletin of the American Physical Society
Annual Meeting of the Four Corners Section of the APS
Volume 58, Number 12
Friday–Saturday, October 18–19, 2013; Denver, Colorado
Session C3: Biological and Soft Condensed Matter Physics I |
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Chair: Kingshuk Ghosh, University of Denver Room: 287 |
Friday, October 18, 2013 11:00AM - 11:24AM |
C3.00001: The ugly truth of enzyme dynamics: coupled chaos and biological function Invited Speaker: Elan Eisenmesser One of the most remarkable findings in the field of protein dynamics has been the discovery that functionally important regions of proteins have evolved to be flexible, yet how such dynamics relate to function still remains obscure at best. Specifically, dynamic movements on the micro-millisecond timescale, otherwise referred to as conformational exchange, are thought to be especially important for enzymes that rely on conformational changes for catalysis. The widely accepted paradigm is that an inherent conformational exchange comprises a highly concerted process that is ``fine-tuned'' to match the catalytic function. However, our studies on multiple enzymes as well as multiple members within an enzyme family suggest that dynamics may instead be a collection of partially coupled dynamic segments tied to the active site. Our lab has even altered dynamic segments distal to an enzyme active site leading to modulated function, providing a proof-of-principle that dynamic segments may be engineered to modify protein function. [Preview Abstract] |
Friday, October 18, 2013 11:24AM - 11:48AM |
C3.00002: Designing Foldable Protein Sequence Through Zipping Contacts Invited Speaker: Sefika Ozkan Earlier experiments suggest that the evolutionary information (conservation of amino acids and coevolution between amino acids) encoded in protein sequences is necessary and sufficient to specify the fold of a protein family. However, there is no computational work to quantify the effect of such evolutionary information on the folding process. Here we simulate a repertoire of native and artificial WW domain sequences using a physics-based protein structure search method called ZAM (Zipping and Assembly method), which samples conformational space effectively towards native-like conformations through zipping and assembly search mechanism. We explore the sequence-structure relationship for WW domains and find that the coevolution information has a remarkable influence on local contacts of N-terminal $\beta $-turn of WW domains . This turn would not form correctly if lack of such information. Moreover, through maximum likelihood approach, we identify five local contacts that play a critical role in folding. Using the contact probability of those five local contacts at the early stage of folding, a classification model is built. This enables us to predict the foldability of a WW sequence with 81{\%} accuracy. Based on this classification model, we re-design the unfoldable WW domain sequences and make them foldable by introducing a few mutations that leads to stabilization of these critical contacts. [Preview Abstract] |
Friday, October 18, 2013 11:48AM - 12:00PM |
C3.00003: Role of native-state dynamics in thermophilic adaptation Lucas Sawle, Kingshuk Ghosh Thermophilic proteins denature at higher temperatures than mesophilic proteins. Among the many hypothesis related to thermophilic adaptation, reduced native state flexibility is one widely believed to be a signature of thermophilic proteins in comparison to their mesophilic homologues. While the majority of existing studies consist of investigating individual proteins, we instead focus on large-scale and detailed modeling of numerous proteins to infer the presence, if any, of general principles to thermophilic adaptation. We have curated and constructed the largest dataset of experimentally determined, monomeric, and non-complexed thermophilic-mesophilic homologue pairs. From this dataset of protein pairs, we performed comparative analysis of the native state fluctuations from molecular dynamics simulations at 300K in explicit solvent. From these dynamical fluctuations at short time scales (up to a cumulative of 300 ns for each protein), we calculated several quantities of interest: i) intra-residue fluctuations, ii) dipole moment fluctuation to calculate dielectric constant and iii) the entropy of the contact distribution. Here, we will present the selective role of these different metrics to distinguish thermophiles from mesophiles. Also, we will present our complementary approach based on thermodynamic analysis of the largest protein stability database, hinting at residual structure in the unfolded state to be an important factor in determining the enhanced stability of thermophiles. [Preview Abstract] |
Friday, October 18, 2013 12:00PM - 12:12PM |
C3.00004: An approach to quantifying macromolecular transition pathways Sean Seyler, Avishek Kumar, Michael Thorpe, Oliver Beckstein Fast transition path sampling methods can mitigate computational obstacles, though the question of whether they can replicate physical ensembles of transitions remains. We introduce a novel method for quantitatively measuring the similarity of transition paths, addressing a need in the computational biophysics community for techniques that facilitate the comparison of the multiplicity of transition path sampling methods. Using the Hausdorff and Fr\'echet path metrics, we quantify distances between piecewise-linear curves in protein configuration space. The dependence of these metrics on temperature (fluctuation size) and the number of particles (coarse-graining level) is tested using a toy model. We then apply our method to the closed/open conformational transition of the enzyme adenylate kinase by analyzing a sample of trajectories produced by a range of different methods. Hierarchical clustering of pairwise path comparisons can distinguish transitions produced by different sampling methods and also group qualitatively similar trajectories generated by variations of the same method. In summary, we present a method to quantitatively classify macromolecular transition pathways, which may assist in the future in evaluating the accuracy of transition path sampling methods. [Preview Abstract] |
Friday, October 18, 2013 12:12PM - 12:24PM |
C3.00005: Lipid Sorting on Curved Supported Lipid Bilayers Using a Nanoparticle Patterned Substrate Philip Cheney, Michelle Knowles Cellular membranes contain a variety of shapes that likely act as motifs for sorting lipids and proteins. To understand the dynamic sorting that takes place within cells, a continuous, fluid bilayer with regions of membrane curvature was designed and characterized using confocal fluorescence and total internal reflection fluorescence microscopy techniques. A supported lipid bilayer was formed over fluorescently labeled nanoparticles deposited on a glass surface. The lipid composition and membrane shape are separately controlled and the nanoparticle dimensions (d $=$ 40-200 nm) determine the extent of curvature. The bulk membrane is fluid as demonstrated by fluorescence recovery after photobleaching using dye labeled lipids. Dye-labeled streptavidin and cholera toxin subunit B are used to track single molecules and clusters of cap-biotinylated DHPE and ganglioside GM1, respectively. The nanoparticle-patterned substrate is a new tool that allows for quantitative measurement of the dynamic interactions between fluorescent biomolecules and regions of membrane curvature using standard dual-color imaging techniques. [Preview Abstract] |
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