Bulletin of the American Physical Society
APS March Meeting 2015
Volume 60, Number 1
Monday–Friday, March 2–6, 2015; San Antonio, Texas
Session F48: Focus Session: Physics of Proteins I |
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Sponsoring Units: DBIO Chair: Dongping Zhong, Ohio State University Room: 217C |
Tuesday, March 3, 2015 8:00AM - 8:12AM |
F48.00001: Reversible cluster formation in concentrated monoclonal antibody solutions P. Douglas Godfrin, Lionel Porcar, Peter Falus, Isidro Zarraga, Norm Wagner, Yun Liu Protein cluster formation in solution is of fundamental interest for both academic research and industrial applications. Recently, industrial scientists are also exploring the effect of reversible cluster formation on biopharmaceutical processing and delivery. However, despite of its importance, the understanding of protein clusters at concentrated solutions remains scientifically very challenging. Using the neutron spin echo technique to study the short time dynamics of proteins in solutions, we have recently systematically studied cluster formation in a few monoclonal antibody (mAb) solutions and their relation with solution viscosity. We show that the existence of anisotropic attraction can cause the formation of finite sized clusters, which increases the solution viscosity. Interestingly, once clusters form at relatively low concentrations, the average size of clusters in solutions remains almost constant over a wide range of concentrations similar to that of micelle formation. For a different mAb we have also investigated, the attraction is mostly induced by hydrophobic patches. As a result, these mAbs form large clusters with loosely linked proteins. In both cases, the formation of clusters all increases the solution viscosity substantially. However, due to different physics origins of cluster formation, solutions viscosities for these two different types of mAbs need to be controlled by different ways. [Preview Abstract] |
Tuesday, March 3, 2015 8:12AM - 8:24AM |
F48.00002: Simultaneous Platinum and Copper Ion Attachment to a Human Copper Chaperone Protein Miroslav Hodak, John Cvitkovic, Corey Yu, Oleg Dmitriev, George Kaminski, Jerry Bernholc Cisplatin is a potent anti-cancer drug based on a platinum ion. However, its effectiveness is decreased by cellular resistance, which involves cisplatin attaching to copper transport proteins. One of such proteins is Atox1, where cisplatin attaches to the copper binding site. Surprisingly, it was shown that both cisplatin and copper can attach to Atox1 at the same time. To study this double metal ion attachment, we use the KS/FD DFT method, which combines Kohn-Sham DFT with frozen-density DFT to achieve efficient quantum-mechanical description of explicit solvent. Calculations have so far investigated copper ion attachment to CXXC motifs present in Atox1. The addition of the platinum ion and the competition between the two metals is currently being studied. These calculations start from a molecular mechanics (MM) structural model, in which glutathione groups provide additional ligands to the Pt ion. Our goals are to identify possible Cu-Pt structures and to determine whether copper/platinum attachment is competitive, independent, or cooperative. Results will be compared to the $^{1}$H, N${^15}$-HSQC NMR experiments, in which binding of copper and cisplatin to Atox1 produces distinct secondary chemical shift signatures, allowing for kinetic studies of simultaneous metal binding. [Preview Abstract] |
Tuesday, March 3, 2015 8:24AM - 8:36AM |
F48.00003: Native dynamics from diversity in NMR structures Heiko Lammert, Jose Onuchic Protein function relies on the characteristic dynamics that arise in the protein's unique native structure, controlled by the smooth, funneled energy landscape evolved to enable fast and reliable folding. Structure-based models draw on energy landscape theory to build an ideally funneled energy landscape only from a protein's native structure. Simplified interactions of homogeneous strength are used to eliminate energetic frustration. The dynamics of the model are controlled by geometric constraints imposed by the native fold. The energy landscapes of many actual proteins are smooth enough to let such unfrustrated models describe their folding mechanisms. But conflicting functional demands upon the sequence may introduce sufficient frustration into the energetics to affect the dynamics. For such cases heterogeneous interactions can be optimized based on additional data. We use the diversity among the conformations deposited in a set of NMR structures to estimate the extent of fluctuations in the native state to build an improved model of protein S6. Qualitative modifications bring the observed mechanism into agreement with experiment, and matching of the entire fluctuation profile leads to similar contact maps as optimization based on either phi-values of sequence data. [Preview Abstract] |
Tuesday, March 3, 2015 8:36AM - 9:12AM |
F48.00004: Redox-controlled proton gating in bovine cytochrome $c$ oxidase Invited Speaker: Jose Onuchic Cytochrome $c$ oxidase is the terminal enzyme in the electron transfer chain of essentially all organisms that utilize oxygen to generate energy. It reduces oxygen to water and harnesses the energy to pump protons across the mitochondrial membrane in eukaryotes and the plasma membrane in prokaryotes. The mechanism by which proton pumping is coupled to the oxygen reduction reaction remains unresolved, owing to the difficulty of visualizing proton movement within the massive membrane-associated protein matrix. Here, with a novel hydrogen/deuterium exchange resonance Raman spectroscopy method, we have identified two critical elements of the proton pump: a proton loading site near the propionate groups of heme $a$, which is capable of transiently storing protons uploaded from the negative-side of the membrane prior to their release into the positive-side of the membrane and a conformational gate that controls proton translocation in response to the change in the redox state of heme$ a$. These findings form the basis for a postulated molecular model describing a detailed mechanism by which unidirectional proton translocation is coupled to electron transfer from heme $a$ to heme $a_{\mathrm{3}}$, associated with oxygen chemistry occurring in the heme $a_{\mathrm{3}}$ site, during enzymatic turnover. Each time heme $a$ undergoes an oxidation-reduction transition a proton is translocated across the membrane accounting for the observation that two protons are translocated during the oxidative phase of the enzymatic cycle and two more are translocated during the reductive phase. This work was done in collaboration with Drs. Tsuyoshi Egawa and Syun-Ru Yeh. [Preview Abstract] |
Tuesday, March 3, 2015 9:12AM - 9:24AM |
F48.00005: Dissecting the relationship between protein structure and sequence variation Amir Shahmoradi, Claus Wilke Over the past decade several independent works have shown that some structural properties of proteins are capable of predicting protein evolution. The strength and significance of these structure-sequence relations, however, appear to vary widely among different proteins, with absolute correlation strengths ranging from $0.1$ to $0.8$. Here we present the results from a comprehensive search for the potential biophysical and structural determinants of protein evolution by studying more than $200$ structural and evolutionary properties in a dataset of $209$ monomeric enzymes. We discuss the main protein characteristics responsible for the general patterns of protein evolution, and identify sequence divergence as the main determinant of the strengths of virtually all structure-evolution relationships, explaining $\sim10-30\%$ of observed variation in sequence-structure relations. In addition to sequence divergence, we identify several protein structural properties that are moderately but significantly coupled with the strength of sequence-structure relations. In particular, proteins with more homogeneous back-bone hydrogen bond energies, large fractions of helical secondary structures and low fraction of beta sheets tend to have the strongest sequence-structure relation. [Preview Abstract] |
Tuesday, March 3, 2015 9:24AM - 9:36AM |
F48.00006: Develop Infrared Structural Biology for Probing Structural Dynamics of Protein Functions Aihua Xie, Zhouyang Kang, Oliver Causey, Charle Liu Protein functions are carried out through a series of structural transitions. Lack of knowledge on functionally important structural motions of proteins impedes our understanding of protein functions. Infrared structural biology is an emerging technology with powerful applications for protein structural dynamics. One key element of infrared structural biology is the development of vibrational structural marker (VSM) database library that translates infrared spectroscopic signals into specific structural information. We report the development of VSM for probing the type, geometry and strength of hydrogen bonding interactions of buried COO- side chains of Asp and Glu in proteins. Quantum theory based first principle computational studies combined with bioinformatic hydrogen bond analysis are employed in this study. We will discuss the applications of VSM in mechanistic studies of protein functions. Infrared structural biology is expected to emerge as a powerful technique for elucidating the functional mechanism of a broad range of proteins, including water soluble and membrane proteins. [Preview Abstract] |
Tuesday, March 3, 2015 9:36AM - 9:48AM |
F48.00007: ABSTRACT WITHDRAWN |
Tuesday, March 3, 2015 9:48AM - 10:00AM |
F48.00008: ABSTRACT WITHDRAWN |
Tuesday, March 3, 2015 10:00AM - 10:12AM |
F48.00009: Building toy models of proteins using coevolutionary information Ryan Cheng, Mohit Raghunathan, Jose Onuchic Recent developments in global statistical methodologies have advanced the analysis of large collections of protein sequences for coevolutionary information. Coevolution between amino acids in a protein arises from compensatory mutations that are needed to maintain the stability or function of a protein over the course of evolution. This gives rise to quantifiable correlations between amino acid positions within the multiple sequence alignment of a protein family. Here, we use Direct Coupling Analysis (DCA) to infer a Potts model Hamiltonian governing the correlated mutations in a protein family to obtain the sequence-dependent interaction energies of a toy protein model. We demonstrate that this methodology predicts residue-residue interaction energies that are consistent with experimental mutational changes in protein stabilities as well as other computational methodologies. Furthermore, we demonstrate with several examples that DCA could be used to construct a structure-based model that quantitatively agrees with experimental data on folding mechanisms. This work serves as a potential framework for generating models of proteins that are enriched by evolutionary data that can potentially be used to engineer key functional motions and interactions in protein systems. [Preview Abstract] |
Tuesday, March 3, 2015 10:12AM - 10:48AM |
F48.00010: Hard-Sphere Models for Predicting Side Chain Conformations of Proteins Invited Speaker: Lynne Regan We now have Angstrom-level resolution of the atomic positions for thousands of protein crystal structures. From these structures, we can determine the probability distributions of the side-chain dihedral angles for each type of amino acid. However, we lack a predictive understanding of these distrbutions, for example, are the shapes of the distributions determined primarily by steric or electrostatic interactions and are they dominated by local interactions within an amino acid or by longer-ranged interactions? Similarly, we do not have a fundamental understanding of what interactions determine the energy barriers that control transitions between either main-chain or side-chain amino acid conformations. To address these questions, we performed all-atom molecular dynamics simulations using a simple model of dipeptides that includes steric interactions plus stereochemical constraints We show that transitions between different backbone or side-chain conformations are strongly coupled to local bond-angle fluctuations. Moreover, the effects are causal, not merely correlative: By fixing the range of the local bond angles sampled, we influence the frequency of transitions in a predictable fashion. These results emphasize the somewhat under-appreciated importance of steric interactions and stereochemical constraints in determining many aspects of protein structure.\\[4pt] In collaboration with Corey O'Hern Diego Caballero, Jennifer Gaines, Alejandro Virrueta and Alice Zhou. [Preview Abstract] |
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