Bulletin of the American Physical Society
APS March Meeting 2016
Volume 61, Number 2
Monday–Friday, March 14–18, 2016; Baltimore, Maryland
Session Y55: Physics of Proteins: Pushing the Envelope on Understanding and Designing FunctionInvited
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Sponsoring Units: DBIO DCOMP DPOLY Chair: Wouter Hoff, Oklahoma State University Room: Hilton Baltimore Holiday Ballroom 6 |
Friday, March 18, 2016 11:15AM - 11:51AM |
Y55.00001: Enhancing MD simulations of proteins using vague and combinatorics information Invited Speaker: Ken Dill We have developed MELD, a method that `melds' together replica-exchange molecular dynamics simulations with external information. Traditionally, accelerating MD simulations has only been possible by using information that is precise and correct. In contrast, MELD allows us to leverage information that is vague or corrupted. For example, we give generic instructives, such as `make a hydrophobic core', `make good secondary structures', or `search only compact structures'. Normally, such information implies a loss of ability to compute free energies and populations. But, MELD satisfies detailed balance. We show that it can fold small proteins much faster than brute-force MD can, that it gives reasonable populations, and that it can succeed in CASP, the blind protein-structure prediction event. [Preview Abstract] |
Friday, March 18, 2016 11:51AM - 12:27PM |
Y55.00002: Molecular and cellular constraints on proteins Invited Speaker: Tanja Kortemme Engineering proteins with new sequences, structures and functions has many exciting practical applications, and provides new ways to dissect design principles for function. Recent successes in computational protein design provide a cause for optimism. Yet many functions are currently too complex to engineer predictively, and successful design of new biological activities also requires an understanding of the functional pressures acting on proteins in the context of cells and organisms. I will present two vignettes describing our progress with dissecting both molecular and cellular constraints on protein function. In the first, we characterized the cost and benefit of protein production upon sequence perturbations in a classic system for gene regulation, the \textit{lac} operon. Our results were unexpected in light of the common assumption that the dominant fitness costs are due to protein \textit{expression}. Instead, we discovered a direct linear relationship between cost and \textit{lac }permease \textit{activity}, not protein or mRNA production. The magnitude of the cost of permease activity, relative to protein production, has consequences for regulation. Our model predicts an advantage of direct regulation of protein \textit{activity} (not just expression), providing a new explanation for the long-known mechanism of ``inducer exclusion'' that inhibits transport through the permease. Similar pressures and cost/benefit tradeoffs may be key to engineering synthetic systems with improved fitness. In the second vignette, I will describe our recent efforts to develop computational approaches that predict protein sequences consistent with multiple functional conformations. We expect such ``multi-constraint'' models to improve predictions of functional sequences determined by deep mutational scanning in bacteria, to provide insights into how the balance between functional conformations shapes sequence space, and to highlight molecular and cellular constraints that cannot be captured by the model. [Preview Abstract] |
Friday, March 18, 2016 12:27PM - 1:03PM |
Y55.00003: Response of proteins to mechanical force Invited Speaker: Dave Thirumalai |
Friday, March 18, 2016 1:03PM - 1:39PM |
Y55.00004: Kinetic Cooperativity, Loop Dynamics, and Allostery from NMR and MD simulations Invited Speaker: Rafael Bruschweiler The hallmark of glucokinase (GCK), which catalyzes the phosphorylation of glucose during glycolysis, is its kinetic cooperativity whose understanding at atomic detail has remained open since its discovery over 40 years ago. I will discuss how the origin of kinetic cooperativity is rooted in intramolecular protein dynamics using NMR relaxation data of 17 isoleucines distributed over all parts of GCK. Residues of glucose-free GCK located in the small domain display a distinct exchange behavior involving multiple conformers that are substantially populated, whereas in the glucose-bound form these dynamic processes are quenched. The conformational exchange process directly competes with the enzymatic turnover at physiological glucose concentrations, thereby generating the sigmoidal rate dependence that defines kinetic cooperativity. The flexible nature of protein loops and the timescales of their dynamics are critical for many biologically important events at the molecular level, such as protein interaction and recognition processes. Based on a library of proteins, rules about loop dynamics in terms of amplitude and timescales can be derived using molecular dynamics (MD) simulations and NMR data. These rules have been implemented in the new web server ToeLoop (for Timescales Of Every Loop) that permits the prediction of loop dynamics based on an average 3D protein structure (http://spin.ccic.ohio-state.edu/index.php/loop/index). [Preview Abstract] |
Friday, March 18, 2016 1:39PM - 2:15PM |
Y55.00005: Unraveling protein catalysis through neutron diffraction. Invited Speaker: Dean Myles Neutron scattering and diffraction are exquisitely sensitive to the location, concentration and dynamics of hydrogen atoms in materials and provide a powerful tool for the characterization of structure-function and interfacial relationships in biological systems. Modern neutron scattering facilities offer access to a sophisticated, non-destructive suite of instruments for biophysical characterization that provide spatial and dynamic information spanning from Angstroms to microns and from picoseconds to microseconds, respectively. Applications range from atomic-resolution analysis of individual hydrogen atoms in enzymes, through to multi-scale analysis of hierarchical structures and assemblies in biological complexes, membranes and in living cells. Here we describe how the precise location of protein and water hydrogen atoms using neutron diffraction provides a more complete description of the atomic and electronic structures of proteins, enabling key questions concerning enzyme reaction mechanisms, molecular recognition and binding and protein-water interactions to be addressed. Current work is focused on understanding how molecular structure and dynamics control function in photosynthetic, cell signaling and DNA repair proteins. We will highlight recent studies that provide detailed understanding of the physiochemical mechanisms through which proteins recognize ligands and catalyze reactions, and help to define and understand the key principles involved. [Preview Abstract] |
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