Bulletin of the American Physical Society
APS March Meeting 2014
Volume 59, Number 1
Monday–Friday, March 3–7, 2014; Denver, Colorado
Session T12: Invited Session: Functional Dynamics of Proteins from Physics to Biology |
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Sponsoring Units: DBIO Chair: Xiang-Qiang Chu, Wayne State University, and Michael Brown, University of Arizona Room: 205 |
Thursday, March 6, 2014 11:15AM - 11:51AM |
T12.00001: Protein Dynamics and Enzyme Catalysis: New results from Theory and Experiment Invited Speaker: Steven Schwartz This talk will focus on recent work identifying enzymes in which rapid protein dynamics are central to the function of chemical catalysis. These motions, on a picosecond timescale, are part of the complex system's reaction coordinate, and so reaction does not occur without them. We also show evidence that such motions is are not simply part of a largely isotropic milieu, but rather special directions in the protein matrix. Theoretical results are coupled to recent experiments that show unequivocally that rapid protein dynamics are not just concomitant with reaction, but are causative. Disruption of these dynamics through mass changes, with no change in the potential energy of the system results in mis-timings of necessary promoting vibrations, and slows the rate of on enzyme chemistry. This is a new paradigm for enzyme function, and perhaps eventually for enzyme design. [Preview Abstract] |
Thursday, March 6, 2014 11:51AM - 12:27PM |
T12.00002: Detecting Protein Dynamics in Various Time Scales by Neutron Scattering Invited Speaker: Xiang-Qiang Chu Proteins undergo sophisticated changes in space and time, in order to keep the cells functioning. These motions are believed to ultimately govern the biological function and activities of the protein. Various tools are used to study the protein dynamics, such as NMR spectroscopy, Raman spectroscopy and Infrared spectroscopy. Among these, neutron scattering provide exceptional tools for studying the structures and dynamics of protein in real time at the molecular level. In our recent research, quasi-elastic neutron scattering (QENS) experiments were carried out to study the protein dynamics by using a ``state-of-the-art'' backscattering spectrometer at the world's largest neutron source at Oak Ridge National Lab (ORNL). As a result, an exotic logarithmic decay in the relaxational dynamics of proteins is observed in the time range of 10ps to 1ns. This is the first experimental observation of logarithmic behavior in protein relaxation. In addition, using a direct time-of-flight Fermi chopper neutron spectrometer (SEQUOIA) at ORNL, we obtained a full map of the milli-eV phonon-like excitations in the fully deuterated protein. The Q range of the observed excitations corresponds to the length scale of about 2.5 to 3 {\AA}, which is close to the length scales of the secondary structures of proteins (4-5 {\AA}) and reflects the collective intra-protein motions. These observations and further investigation using neutron scattering can reveal important macromolecular behavior that cannot be otherwise measured by other techniques. [Preview Abstract] |
Thursday, March 6, 2014 12:27PM - 1:03PM |
T12.00003: Multiscale Dynamics of Enzyme Catalysis and Sec-Faciliated Protein Translocation Invited Speaker: Thomas Miller Nature exhibits dynamics that span extraordinary ranges of space and time. In some cases, these dynamical hierarchies are well separated, simplifying their understanding and description. But chemistry and biology are replete with examples of dynamically coupled scales. In this talk, we will discuss new simulation methods that enable the inclusion of nuclear quantum effects, such as zero point energy and tunneling, in the reaction dynamics of enzymes, as well as coarse-graining strategies to enable minute-timescale simulations of protein targeting to cell membranes. [Preview Abstract] |
Thursday, March 6, 2014 1:03PM - 1:39PM |
T12.00004: Conformational Fluctuations in G-Protein-Coupled Receptors Invited Speaker: Michael F. Brown G-protein\textbf{-}coupled receptors (GPCRs) comprise almost 50{\%} of pharmaceutical drug targets, where rhodopsin is an important prototype and occurs naturally in a lipid membrane. Rhodopsin photoactivation entails 11-\textit{cis} to all-\textit{trans} isomerization of the retinal cofactor, yielding an equilibrium between inactive Meta-I and active Meta-II states. Two important questions are: (1) Is rhodopsin is a simple two-state switch? Or (2) does isomerization of retinal unlock an activated conformational ensemble? For an ensemble-based activation mechanism (EAM) [1] a role for conformational fluctuations is clearly indicated. Solid-state NMR data together with theoretical molecular dynamics (MD) simulations detect increased local mobility of retinal after light activation [2]. Resultant changes in local dynamics of the cofactor initiate large-scale fluctuations of transmembrane helices that expose recognition sites for the signal-transducing G-protein. Time-resolved FTIR studies and electronic spectroscopy further show the conformational ensemble is strongly biased by the membrane lipid composition, as well as pH and osmotic pressure [3]. A new flexible surface model (FSM) describes how the curvature stress field of the membrane governs the energetics of active rhodopsin, due to the spontaneous monolayer curvature of the lipids [4]. Furthermore, influences of osmotic pressure dictate that a large number of bulk water molecules are implicated in rhodopsin activation. Around 60 bulk water molecules activate rhodopsin, which is much larger than the number of structural waters seen in X-ray crystallography, or inferred from studies of bulk hydrostatic pressure. Conformational selection and promoting vibrational motions of rhodopsin lead to activation of the G-protein (transducin). Our biophysical data give a paradigm shift in understanding GPCR activation. The new view is: dynamics and conformational fluctuations involve an ensemble of substates that activate the cognate G-protein in the amplified visual response.\\[4pt] [1] A. V. Struts et al. (2011) \textit{Nat. Struct. Mol. Biol.} \textbf{18}, 392.\\[0pt] [2] A. V. Struts et al. (2011)~\textit{PNAS}$~$\textbf{108}, 8263.\\[0pt] [3] M. Mahalingam et al. (2008) \textit{PNAS} \textbf{105}, 17795.\\[0pt] [4] M. F. Brown (2012) \textit{Biochemistry} \textbf{51}, 9782. [Preview Abstract] |
Thursday, March 6, 2014 1:39PM - 2:15PM |
T12.00005: Pulse Dipolar ESR and Protein Superstructures and Function Invited Speaker: Jack Freed Pulse dipolar electron-spin resonance (PDS-ESR) has emerged as a powerful methodology for the study of protein structure and function. This technology, in the form of double quantum coherence (DQC) -- ESR and double-electron-electron resonance (DEER) in conjunction with site-directed spin-labeling will be described. It enables the measurement of distances and their distributions in the range of 1-9 nm between pairs of spins labeled at two sites in the protein. Many biological objects can be studied: soluble and membrane proteins, protein complexes, etc. Many sample morphologies are possible: uniform, heterogeneous, etc. thereby permitting a variety of sample types: solutions, liposomes, micelles, bicelles. Concentrations from micromolar to tens of millimolar are amenable, requiring only small amounts of biomolecules. The distances are quite accurate, so a relatively small number of them are sufficient to reveal structures and functional details. Several examples will be shown. The first is defining the protein complexes that mediate bacterial chemotaxis, which is the process whereby cells modulate their flagella-driven motility in response to environmental cues. It relies on a complex sensory apparatus composed of transmembrane receptors, histidine kinases, and coupling proteins. PDS-based models have captured key architectural features of the receptor kinase arrays and the flagellar motor, and their changes in conformation and dynamics that accompany kinase activation and motor switching. Another example will be determining the conformational states and cycling of a membrane transporter, GltPh, which is a homotrimer, in its apo, substrate-bound, and inhibitor-bound, states in membrane vesicles providing insight into its energetics. In a third example the structureless (in solution) proteins alpha-synuclein and tau, which are important in Parkinson's disease and in neurodegeneration will be described and the structures they take on in contact with membranes will be described. Another important development is that of extending ESR to much higher frequencies (ca. 250 GHz), which has enabled a multi-frequency ESR approach to the study of protein dynamics that enables the separation of their complex modes of motion in terms of their different time scales. [Preview Abstract] |
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