Bulletin of the American Physical Society
APS March Meeting 2013
Volume 58, Number 1
Monday–Friday, March 18–22, 2013; Baltimore, Maryland
Session Y46: Focus Session: Physics of Proteins III |
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Sponsoring Units: DBIO DPOLY Chair: Corey O'Hern, Yale University Room: Hilton Baltimore Holiday Ballroom 5 |
Friday, March 22, 2013 8:00AM - 8:12AM |
Y46.00001: Copper Chelation in Alzheimer's Disease Protein Frisco Rose, Miroslav Hodak, Jerry Bernholc Alzheimer's disease (AD) is a neurodegenerative disorder affecting millions of people in the U.S. AD is primarily characterized at the cellular level by densely tangled fibrils of amyloid-$\beta$ protein. These protein clusters have been found in association with elevated levels of multiple transition metals, with copper being the most egregious. Interestingly, metal chelation has shown promise in attenuating the symptoms of AD in recent clinical studies. We investigate this process by constructing an atomistic model of the amyloid-$\beta$-copper complex and profile the energetic viability in each of its subsequent disassociation stages. Our results indicate that five energetic barriers must be overcome for full metal chelation. The energy barriers are biologically viable in the presence water mediated bond and proton transfer between the metal and the protein. We model the chelation reaction using a consecutive path nudged elastic band method implemented in our {\it ab initio} real-space multi-grid code to obtain a viable sequence. This reaction model details a physically consistent explanation of the chelation process that could lead to the discovery of more effective chelation agents in the treatment of AD. [Preview Abstract] |
Friday, March 22, 2013 8:12AM - 8:24AM |
Y46.00002: Low resolution structures of cold, warm, and chemically denatured cytochrome-c via SAXS Christopher Asta, Anthony Banks, Margaret Elmer, Trevor GrandPre, Eric Landahl The results of a small-angle x-ray scattering (SAXS) study of equine cytochrome-c protein under different unfolding conditions are discussed. Although the measured radius of gyration of this protein over a wide range of temperatures and GuHCl concentrations conform to a two-state model, we find different levels of residual structure present depending on whether the protein is cold- or warm- denatured. We present DAMMIF reconstructions of these different unfolded states using 1532 dummy atoms with a 1.5 Angstrom radius, and suggest ways that these different states may be described by the same folding free energy. [Preview Abstract] |
Friday, March 22, 2013 8:24AM - 9:00AM |
Y46.00003: Structural dynamics of membrane proteins - time-resolved and surface-enhanced IR spectroscopy Invited Speaker: Joachim Heberle Membrane proteins are the target of more than 50{\%} of all drugs and are encoded by about 30{\%} of the human genome. Electrophysiological techniques, like patch-clamp, unravelled many functional aspects of membrane proteins but suffer from structural sensitivity. We have developed Surface Enhanced Infrared Difference Absorption Spectroscopy (SEIDAS) to probe potential-induced structural changes of a protein on the level of a monolayer. A novel concept is introduced to incorporate membrane proteins into solid supported lipid bilayers in an orientated manner via the affinity of the His-tag to the Ni-NTA terminated gold surface. General applicability of the methodological approach is shown by tethering photosystem II to the gold surface. In conjunction with hydrogenase, the basis is set towards a biomimetic system for hydrogen production. Recently, we succeeded to record IR difference spectra of a monolayer of sensory rhodopsin II under voltage-clamp conditions. This approach opens an avenue towards mechanistic studies of voltage-gated ion channels with unprecedented structural and temporal sensitivity. Initial vibrational studies on the novel light-gated channelrhodopsin-2 (ChR2) will be presented. ChR2 represents a versatile tool in the new field of optogenetics where physiological reactions are controlled by light. [Preview Abstract] |
Friday, March 22, 2013 9:00AM - 9:12AM |
Y46.00004: Multistage Enzymatic Pathways of the Copper-containing Nitrite Reductase (CuNiR) Yan Li, Miroslav Hodak, Jerry Bernholc Copper-containing nitrite reductase (CuNiR) catalyzes the reduction of NO$_2^-$ to NO in the global nitrogen cycle. Experimental X-ray data have provided good insight into the overall function of CuNiR. However, many important questions, such as the relevance of the conformational change of Asp$^{98}$ as well as the transformation from the O-coordination of the substrate to the N-coordination of the product remain unanswered. We present a computational study of the enzymatic mechanism of CuNiR based on density functional theory. The climbing-image nudged elastic band (CI-NEB) method is used to find the minimum energy pathways and the activation energy barriers of the reaction. Furthermore, the effects of hybrid functionals and solvent on the activation barriers are investigated. A critical residue Asp$^{98}$ is found to control the access to the binding site and to stabilize a previously reported ``side-on'' coordination of the nitrosyl intermediate, although this geometry does not occur during the reaction. We also find that the transformation of the O- to N-attachment is achieved by an electron transfer from Type I copper. [Preview Abstract] |
Friday, March 22, 2013 9:12AM - 9:24AM |
Y46.00005: Single molecule processivity and dynamics of cAMP-dependent protein kinase (PKA) Patrick C. Sims, Yongki Choi, Chengjun Dong, Issa S. Moody, Mariam Iftikhar, O. Tolga Gul, Gregory A. Weiss, Philip G. Collins Using single-walled carbon nanotube (SWNT) transistors, we monitored the processivity and dynamics of single molecules of cAMP-dependent protein kinase (PKA). As PKA enzymatically phosphorylates its peptide substrate, it generates an electronic signal in the transistor that can be monitored continuously and with 20 $\mu $s resolution. The electronic recording directly resolves substrate binding, ATP binding, and cooperative formation of PKA's catalytically functional, ternary complex. Statistical analysis of many events determines on- and off-rates for each of these events, as well as the full transistion probability matrix between them. Long duration monitoring further revealed minute-to-minute rate variability for a single molecule, and different mechanistic statistics for ATP binding than for substrate. The results depict a highly dynamic enzyme offering dramatic possibilities for regulated activity, an attribute that is useful for an enzyme that plays crucial roles in cell signaling. [Preview Abstract] |
Friday, March 22, 2013 9:24AM - 9:36AM |
Y46.00006: The ribosome as an optimal decoder: a lesson in molecular recognition Tsvi Tlusty, Yonatan Savir The ribosome is a complex molecular machine that, in order to synthesize proteins, has to decode mRNAs by pairing their codons with matching tRNAs. Decoding is a major determinant of fitness and requires accurate and fast selection of correct tRNAs among many similar competitors. However, it is unclear whether the present ribosome, and in particular its large deformations during decoding, are the outcome of adaptation to its task as a decoder or the result of other constraints. Here, we derive the energy landscape that provides optimal discrimination between competing substrates, and thereby optimal tRNA decoding. We show that the measured landscape of the prokaryotic ribosome is indeed sculpted in this way. This suggests that conformational changes of the ribosome and tRNA during decoding are means to obtain an optimal decoder. Our analysis puts forward a generic mechanism that may be utilized by other ribosomes and other molecular recognition systems. [Preview Abstract] |
Friday, March 22, 2013 9:36AM - 9:48AM |
Y46.00007: A Bayesian Statistical Approach for Improving Scoring Functions for Protein-Ligand Interactions Sam Z Grinter, Xiaoqin Zou Even with large training sets, knowledge-based scoring functions face the inevitable problem of sparse data. In this work, we present a novel approach for handing the sparse data problem, which is based on estimating the inaccuracy caused by sparse count data in a potential of mean force (PMF). Our new scoring function, STScore, uses a consensus approach to combine a PMF with a simple force-field-based potential (FFP), where the relative weight given to the PMF and FFP is a function of their estimated inaccuracies. This weighting scheme implies that less weight will be given to the PMF for any pairs or distances that occur rarely in the training data, thus providing a natural way to deal with the sparse data problem. Simultaneously, by providing the FFP as a substitute, the method provides an improved approximation of the interactions between rare chemical groups, which tend to be excluded or reduced in influence by purely PMF-based approaches. Using several common test sets for protein-ligand interaction studies, we demonstrate that this sparse data method effectively combines the PMF and FFP, exceeding the performance of either potential alone, and is competitive with other commonly-used sparse data methods. [Preview Abstract] |
Friday, March 22, 2013 9:48AM - 10:00AM |
Y46.00008: Refinement and Selection of Near-native Protein Structures Jiong Zhang, Jingfen Zhang, Yi Shang, Dong Xu, Ioan Kosztin In recent years \textit{in silico} protein structure prediction reached a level where a variety of servers can generate large pools of near-native structures. However, the identification and further refinement of the best structures from the pool of decoys continue to be problematic. To address these issues, we have developed a selective refinement protocol (based on the Rosetta software package), and a molecular dynamics (MD) simulation based ranking method (MDR). The refinement of the selected structures is done by employing Rosetta's relax mode, subject to certain constraints. The selection of the final best models is done with MDR by testing their relative stability against gradual heating during all atom MD simulations. We have implemented the selective refinement protocol and the MDR method in our fully automated server Mufold-MD. Assessments of the performance of the Mufold-MD server in the CASP10 competition and other tests will be presented. [Preview Abstract] |
Friday, March 22, 2013 10:00AM - 10:12AM |
Y46.00009: ABSTRACT HAS BEEN MOVED TO H1.00345 |
Friday, March 22, 2013 10:12AM - 10:24AM |
Y46.00010: Diffusion and internal dynamics of proteins in crowded solutions Felix Roosen-Runge, Marcus Hennig, Tilo Seydel, Fajun Zhang, Frank Schreiber Protein function is determined through the interplay of structure, dynamics and the aqueous, but crowded cellular environment. We present a comprehensive study accessing the full hierarchy of protein dynamics in solutions, e.g. vibrations, interdomain motions and diffusion of the entire protein. Quasi-elastic neutron and dynamic light scattering experiments are performed and compared to theoretical predictions. In crowded solutions, both self diffusion $D_s$ and collective diffusion $D_c$ of protein solutions are well described by colloidal concepts, with $D_s$ reduced to $20 \%$ at $\approx 20 \%$ volume fraction [1,2]. Separating the motion of the entire protein molecule, the internal motions are accessed under native conditions [3]. We studied the dynamics before, during and after thermal denaturation, supporting the notion of protein unfolding with subsequent chain entanglement. While long-range motions are {\it reduced} in the denatured state, the local flexibility of side chains is found to be {\it enhanced}. The frameworks enable further experimental access to the relation of protein function and dynamics at fast time scales. [1] F. Roosen-Runge et al., PNAS 108 (2011) 11815; [2] M. Heinen et al., Soft Matter 8 (2012) 1404; [3] M. Hennig et al., Soft Matter 8 (2012) 1628 [Preview Abstract] |
Friday, March 22, 2013 10:24AM - 10:36AM |
Y46.00011: Diffusion of molecular oxygen in the red fluorescent protein mCherry Chola Regmi, Yuba Bhandari, Bernard Gerstman, Prem Chapagain The monomeric variants of red fluorescent proteins (RFPs), known as mFruits, have been especially valuable for tagging and tracking cellular processes \textit{in vivo. } Determining the oxygen diffusion pathways in FPs can be important for improving photostability and for understanding maturation of the chromophore. We use molecular dynamics (MD) calculations to investigate the diffusion of molecular oxygen in one of the most useful monomeric RFPs, mCherry. We investigate a pathway that allows oxygen molecules to enter from the solvent and travel through the protein barrel to the chromophore. The pathway contains several oxygen hosting pockets, which are identified by the amino acid residues that form the pocket. The results provide a better understanding of the mechanism of molecular oxygen access into the fully folded mCherry protein barrel and provide insight into the one of the photobleaching processes in this protein. [Preview Abstract] |
Friday, March 22, 2013 10:36AM - 10:48AM |
Y46.00012: New insights into the picosecond dynamics solvated proteins Nguyen Vinh, Jim Allen, Kevin Plaxco According to computer simulations, the slowest, largest-scale harmonic motions of solvated biomolecules and the relaxation times of water occur on the picosecond regime. Experimental methods for the characterization of these collective vibrational modes, however, have been severely lacking. In response, we have developed a unique precision and sensitivity dielectric spectrometer. Operating over the frequency range from 0.5 GHz up to 1.1 THz, this spectrometer provides an unparalleled ability to probe the dynamics of water and aqueous proteins over the 100 fs to 100 ps timescale. Using this spectrometer to characterize the collective dynamics of solvated lysozyme we find that the collective vibrational modes of this protein are characterized by a hitherto unrecognized cutoff at 250 GHz (corresponding to 0.6 ps) arising due to the finite size of the molecule. Employing an effective medium approximation to describe the complex dielectric response of the protein in solution we find that each molecule is surrounded by a tightly held layer of 164 $\pm$ 5 water molecules that behave as if they are an integral part of the protein. The observation sheds new light on the femtosecond to picosecond collective dynamics of water and solvated biomolecules. [Preview Abstract] |
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