Bulletin of the American Physical Society
APS March Meeting 2017
Volume 62, Number 4
Monday–Friday, March 13–17, 2017; New Orleans, Louisiana
Session K6: Physics of Proteins Association and Recognition IFocus
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Sponsoring Units: DBIO DPOLY Chair: Loren Hough, University of Colorado Room: 265 |
Wednesday, March 15, 2017 8:00AM - 8:12AM |
K6.00001: Stochastic Protein Multimerization, Cooperativity and Fitness Kyle Hagner, Sima Setayeshgar, Michael Lynch Many proteins assemble into multimeric structures that can vary greatly among phylogenetic lineages. As protein-protein interactions (PPI) require productive encounters among subunits, these structural variations are related in part to variation in cellular protein abundance. The protein abundance in turn depends on the intrinsic rates of production and decay of mRNA and protein molecules, as well as rates of cell growth and division. We present a stochastic model for prediction of the multimeric state of a protein as a function of these processes and the free energy associated with binding interfaces. We demonstrate favorable agreement between the model and a wide class of proteins using E. coli proteome data. As such, this platform, which links protein abundance, PPI and quaternary structure in growing and dividing cells can be extended to evolutionary models for the emergence and diversification of multimeric proteins. We investigate cooperativity - a ubiquitous functional property of multimeric proteins - as a~possible selective force driving multimerization, demonstrating a reduction in the cost of protein production relative to the overall proteome energy budget that can be tied to fitness. [Preview Abstract] |
Wednesday, March 15, 2017 8:12AM - 8:24AM |
K6.00002: Mechanistic pathways of recognition of a solvent-inaccessible cavity of protein by a ligand Jagannath Mondal, Subhendu Pandit, Bhupendra Dandekar, Pramodh Vallurupalli One of the puzzling questions in the realm of protein-ligand recognition is how a solvent-inaccessible hydrophobic cavity of a protein gets recognized by a ligand. We address the topic by simulating, for the first time, the complete binding process of benzene from aqueous media to the well-known buried cavity of L99A T4 Lysozyme at an atomistic resolution. Our multiple unbiased microsecond-long trajectories, which were completely blind to the location of target binding site, are able to unequivocally identify the kinetic pathways along which benzene molecule meanders across the solvent and protein and ultimately spontaneously recognizes the deeply buried cavity of L99A T4 Lysozyme at an accurate precision. Our simulation, combined with analysis based on markov state model and free energy calculation, reveals that there are more than one distinct ligand binding pathways. Intriguingly, each of the identified pathways involves the transient opening of a channel of the protein prior to ligand binding. The work will also decipher rich mechanistic details on unbinding kinetics of the ligand as obtained from enhanced sampling techniques. [Preview Abstract] |
Wednesday, March 15, 2017 8:24AM - 8:36AM |
K6.00003: Polymorphism of Protein Aggregation: From Amyloid Fibrils to Crystallization Mohammad S Safari, Jacinta C Conrad, Peter G Vekilov Protein aggregation is commonly observed in neurological diseases and in different types of cancer. Despite the established mechanism of amyloid formation, the polymorphism of aggregation is not very well understood; improved knowledge of mechanisms for aggregation that operate in vivo or under physiological conditions is likely to inform therapeutic design. Here we show that reduction of disulfide bonds in lysozyme can lead to formation of gel-like oligomers that are precursors for protein crystal nucleation events. The growth in size of oligomers follows slow first-order kinetics, suggesting that monomers with free thiol contribute to formation of clusters. Free thiol concentration measurements showed that the thiol concentration was relatively stable over 12 hr, confirming the slow kinetics was due to gelation inside the clusters. We probed the hydrophobicity of the clusters using ANS and ThT assays, and showed that the protein conformation in these clusters differs from that of thermally denatured aggregates. Although partial unfolding aids the formation of precursors to both amyloids and crystals, our results suggest that these pathways exhibit distinct signatures even at the earliest stages. [Preview Abstract] |
Wednesday, March 15, 2017 8:36AM - 9:12AM |
K6.00004: Rate Constants and Mechanisms of Protein-Ligand Binding Invited Speaker: Huan-Xiang Zhou Whereas protein-ligand binding affinities have long established prominence, binding rate constants and binding mechanisms have continued to gain increasing attention in recently years. Both new computational methods and new experimental techniques have been developed to characterize the latter properties. It is now realized that, binding mechanisms, like binding rate constants, can and should be quantitatively determined. In this talk, I will summarize studies and synthesize ideas on several topics, in the hope of providing a coherent picture and physical insight on binding kinetics. The topics include: microscopic formulation of the kinetic problem and its reduction to simple rate equations; computation of binding rate constants; quantitative determination of binding mechanisms; and elucidation of physical factors that control binding rate constants and mechanisms. [Preview Abstract] |
Wednesday, March 15, 2017 9:12AM - 9:24AM |
K6.00005: Protein Folding and Unfolding Dynamics from Direct Energy Landscape Sampling Simulations Nathan Walter, Yang Zhang Attempts to capture the protein folding-unfolding process at the atomic scale are limited due to the temporal constraints of molecular dynamics simulations. Herein, we circumvent this temporal limitation by using a history-dependent metadynamics algorithm to directly sample the potential-energy landscape of several proteins. Previous applications of the original metadynamics method to proteins penalized select collective variables or dihedral angles of the protein assumed to be the principles to the folding process. Rather, our method penalizes the full coordinate space of the protein resulting in a 3N-dimensional sampled energy-landscape. The sampled timescale of the landscape is orders of magnitude longer than molecular dynamics simulations, which allows the observation of the folding and unfolding process multiple times during the simulation. From the sampled energy landscape, we can predict the folded state of the protein, and the activation barrier and the timescale associated with the folding and unfolding processes of the protein. Herein, we will present these findings for several well-studied proteins, to validate our results, and several new proteins, as a novel extension. [Preview Abstract] |
Wednesday, March 15, 2017 9:24AM - 9:36AM |
K6.00006: pH-dependent Conformational Reorganization due to Ionizable Residues in a Hydrophobic Protein Interior. Ankita Sarkar, Pancham Lal Gupta, Adrian Roitberg Ionizable residues in proteins are intrinsically hydrophilic. However, ionizable residues buried in the protein interior, despite being inherently incompatible with hydrophobic environments, are responsible for major protein functions like biological energy transduction and reactions in enzymatic pathways. These buried ionizable residues display anomalous experimental pKa values. In the present work, we study the pH-dependent conformational reorganizations coupled to the ionization of lysine residues in L25K and L125K variants of staphylococcal nuclease (SNase) using constant pH replica exchange molecular dynamics simulations (pH-REMD) in explicit solvent. Our calculations show that the pKa values of lysine residues buried in the 25$^{\mathrm{th}}$ and 125$^{\mathrm{th}}$ positions of the L25K and L125K respectively, are significantly deviated from their pKa values in bulk water and are in good agreement with experimental values. This computational study, besides offering a detailed atomistic understanding of the structural determinants of the shifted pKa values displayed by internal ionizable residues, aids in bolstering the experimental findings. [Preview Abstract] |
(Author Not Attending)
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K6.00007: Computing the binding affinity of Zn$^{\mathrm{\mathbf{2+}}}${ in human carbonic anhydrase II on the basis of all-atom molecular dynamics simulations.} Thierry Wambo, Roberto Rodriguez Human carbonic anhydrase II (hCAII) is a metalloenzyme with a Zinc cation at its binding site. The presence of the Zinc turns the protein into an efficient enzyme which catalyzes the reversible hydration of carbon dioxide into bicarbonate anion. Available X-ray structures of the apo-hCAII and holo-hCAII show no significant differences in the overall structure of these proteins. What difference, if any, is there between the structures of the hydrated apo-hCAII and holo? How can we use computer simulation to efficiently compute the binding affinity of Zinc to hCAII? We will present a scheme developed to compute the binding affinity of Zinc cation to hCAII on the basis of all-atom molecular dynamics simulation where Zinc is represented as a point charge and the CHARMM36 force field is used for running the dynamics of the system. Our computed binding affinity of the cation to hCAII is in good agreement with experiment, within the margin of error, while a look at the dynamics of the binding site suggests that in the absence of the Zinc, there is a re-organization of the nearby histidine residues which adopt a new distinct configuration. [Preview Abstract] |
Wednesday, March 15, 2017 9:48AM - 10:00AM |
K6.00008: In-silico stress-strain measurements on beta-solenoid protein lattice Rachel Baarda, Daniel Cox Due to their large material strength and potential for functionalization, beta solenoid proteins show promise as building blocks in biomaterials applications such as two- and three- dimensional scaffolds. We have designed a two-dimensional hexagonal lattice by covalently linking a beta solenoid protein, spruce budworm antifreeze protein (SBAFP), to a viral protein (4NCV) with C3 symmetry. Although the properties of individual SBAFP segments have previously been studied, the composite properties of this lattice had not. We use the molecular dynamics tool Gromacs to strain the lattice by deforming the simulation cell and measure the resulting stress. Periodic boundary conditions allow us to simulate an infinite lattice; implicit solvent is used to remove the effects of fluid strain on the results. Stress is computed as twice the difference between the virial and the kinetic energy over the volume of the simulation cell. We evaluate stress-strain curves for the diagonal elements to extract the corresponding elastic modulus. [Preview Abstract] |
Wednesday, March 15, 2017 10:00AM - 10:12AM |
K6.00009: Single Molecule Dynamics in a Model Glycocalyx Jan Scrimgeour, Dylan Young The glycocalyx of endothelial cells is a hyaluronan-rich polymer brush that acts as a mechanical interface between the dynamic flow of blood through the vascular system and the endothelial cell surface, and is postulated to play an essential roll in mechano-sensing, shear flow moderation and molecular filtering. The brush is formed by long hyaluronan molecules that are extruded through the cell membrane, and is structured by the tethering of large proteoglycans, such as versican, to the hyaluronan, causing the brush to swell to a thickness in excess of 4 micrometers. This long length scale combined with the high molecular weight of the brush’s constituents make the dynamics of this system accessible to particle tracking microscopy. We present a platform for the investigation of glycocalyx dynamics at the single molecule level. The platform integrates a synthetic biopolymer brush tethered to a hydrogel cushion within a microfluidic system that is capable of exposing the brush to complex pulsatile flow. Single molecule imaging allows the dynamics of individual proteoglycans within the brush to be visualized, and offers insight into the microscopic structure of this soft material interface. [Preview Abstract] |
Wednesday, March 15, 2017 10:12AM - 10:24AM |
K6.00010: Single molecule force spectroscopy reveals the adhesion mechanism of hydrophobins Yi Cao, Bing Li, Meng Qin, Wei Wang Hydrophobins are a special class of amphiphilic proteins produced by filamentous fungi. They show outstanding interfacial self-assembly and adhesion properties, which are critical to their biological function. Such feature also inspires their broad applications in bio-engineering, surface modification, and nanotechnology. However, the biophysical properties of hydrophobins are not well understood. We combined atomic force microscopy based single molecule force spectroscopy and protein engineering to directly quantify the adhesion strength of a hydorphobin (HFB1) to various surfaces in both the monomer and oligomer states to reveal the molecular determinant of the adhesion strength of hydrophobins. We found that the monomer HFB1 showed distinct adhesion properties towards hydrophobic and hydrophilic surfaces. The adhesion to hydrophobic surfaces (i.e. graphite and gold) was significantly higher than that to the hydrophilic ones (e.g. mica and silicon). However, when self-assembled monolayers were formed, the adhesion strengths to various surfaces were similar and were ubiquitously stronger than the monomer cases. We hypothesized that the interactions among hydrophobins in the monolayer played significant roles for the enhance adhesion strengths. Extracting any single hydrophobin monomers from the surface required the break of interactions not only with the surface but also with the neighboring units. We proposed that such a mechanism may be widely explored in nature for many biofilms for surface adhesion. May also inspire the design of novel adhesives. [Preview Abstract] |
Wednesday, March 15, 2017 10:24AM - 10:36AM |
K6.00011: New Model for Deep Indentation by Spherical AFM probes Kiarash Rahmani Eliato, Bryant Doss, Harpinder Saini, Mehdi Nikkhah, Robert Ros Atomic Force Microscopy based microrheology has evolved as a key tool in the study of mechanics of biological materials. Spherical probes and contact models such as the Hertz model [1] are commonly used for soft materials, such as cells and hydrogels. Hertz model is limited to shallow indentations due to its first order geometry approximation. Deep indentation provides additional information like mechanical heterogeneity. In this study, we present a novel model using the second-order approximation of the sphere geometry and Sneddon's solution [2]. Polyacrylamide gels were used to collect experimental data both, for quasi-static (elastic moduli) and dynamic (shear storage and loss moduli) quantifications. We verified the model by finite element simulations. Our model demonstrates constant elastic moduli and more homogenous shear storage moduli up to the radius of the probe, while the elastic and shear storage modulus calculated with the Hertz model decrease with the indentation depth. Applications of this model to various hydrogels will be shown. We anticipate that the proposed model improves the precession of microrheology with spherical probes. 1. Hertz, H.,J. f\"{u}r die R. Angew. Math. 92, 156 (1882) 2. Sneddon, I.N., Int.J.Eng.Sci 3, 47 (1965) [Preview Abstract] |
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