Session TOG. There are 5 abstracts in this session.

Session: COMPUTATION/THEORY 1, time: 4:00 - 4:25 pm

Computer Assisted 3D Structure Elucidation (CASE-3D) Using Isotropic and Anisotropic NMR Parameters for the Structural Analysis of Small Molecules

Roberto R. Gil
Carnegie Mellon University, Pittsburgh, PA

A multiNMR parameters fitting methodology called CASE-3D (Computer Assisted 3D Structure Elucidation) will be presented. The method performs configuration/conformation selection using Chemical Shifts, J Couplings, NOE-derived distances, Residual Dipolar Couplings (RDCs) and Residual Chemical Shift Anisotropies. This tool has been succesfully applied to the structural analysis of small molecules in Organic Synthesis, Natural Products and Medicinal Chemistry.

Session: COMPUTATION/THEORY 1, time: 4:25 - 4:50 pm

Dynameomics: Discovery of a New Secondary Structure and the Design and Characterization of Amyloid Inhibitors and Diagnostics

Valerie Daggett
University Of Washington, ,

We have been involved in the development and use of realistic computer simulations of proteins to characterize the conformational changes associated with amyloid formation. In so doing we discovered a novel structure adopted by amyloidogenic proteins, but not ‘normal’ proteins, and we proposed that it defines the toxic soluble oligomers formed en route to the nontoxic mature fibrils. As such, this structure, which we call α-sheet, represents a new target for amyloid therapeutics and diagnostics. We have designed, synthesized, and tested compounds to be complementary to this ‘toxic’ structure and they inhibit aggregation in unrelated amyloid systems by specifically binding the toxic oligomers, which in turn neutralizes the toxic species. These α-sheet compounds represent a novel platform for attacking these diseases and the hope of disease-modifying treatments and early diagnosis.

Session: COMPUTATION/THEORY 1, time: 4:50 - 5:05 pm

Observing Functional Protein Motions on Unchartered Timescales by Nanoparticle-Assisted NMR Spin Relaxation

Rafael Bruschweiler
Ohio State University, Columbus, OH

Multidimensional NMR relaxation experiments have played a pivotal role for the characterization of structural dynamics of many different proteins and their critical role in protein function. However, for nuclear spin physics reasons the observation of motions on timescales ranging from tens of nanoseconds to microseconds have remained elusive. A novel approach will be described that opens up this timescale window by the use of silica nanoparticles that transiently interact with the proteins of interest in solution. It is demonstrated how nanoparticle-assisted spin relaxation is able to uncover novel types of protein motions that were previously unobservable and how such motions can be validated using molecular dynamics (MD) simulations.

Session: COMPUTATION/THEORY 1, time: 5:05 - 5:20 pm

Combining a polarizable force field and experimental data to improve the prediction of NMR spin relaxation parameters

Moreno Marcellini; Minh-Ha Nguyen; Marie Martin; Maggy Hologne; Olivier Walker
University of Lyon, Villeurbanne, France

Solution NMR is a powerful technique to observe biomolecular dynamics across ps−ns time scales with the measurement of the well-known R1, R2 and 1H-15N steady-state heteronuclear NOEs. We have recently demonstrated that the prediction of raw NMR spin relaxation parameters is possible with molecular dynamics simulations that uses empirical force fields where electrostatics are treated as fixed point charge. Another degree of improvement is added with the use of the AMOEBA polarizable force field that allows a more sophisticated functional form of the electrostatic interactions. We show that the use of the AMOEBA polarizable force field, combined with experimental rotational diffusion improves the prediction of NMR spin relaxation parameters.

Session: COMPUTATION/THEORY 1, time: 5:20 - 5:35 pm

Spin Relaxation and Molecular Dynamics Simulations Reveal a Synergistic Relationship Between Water Dynamics and Functional Motions in Intrinsically Disordered Proteins

Nicola Salvi; Wiktor Adamski; Anton Abyzov; Malene R. Jensen; Martin Blackledge
Institut de Biologie Structurale, Grenoble, FR

Solvent plays a fundamental role in determining protein dynamics. In particular, functional dynamics of intrinsically disordered proteins (IDPs) depends crucially on their molecular environment.

Using 15N spin relaxation measurements and temperature-dependent molecular dynamics simulations, we derive a unified description of IDP dynamics under near-physiological conditions. We show that dynamics is highly dependent on the lifetime of hydrogen bonds formed by water molecules, suggesting that biomolecules and hydrotropes, which are present in physiological conditions and modulate the plasticity of hydrogen bond networks, also modulate IDP dynamics.

Indeed, we use 15N  relaxation measurements at multiple temperatures and crowding concentrations to develop a model of protein motions as a function of temperature and solvent friction and apply it to in-cellulo 15N relaxation rates, providing an accurate assessment of functionally important IDP dynamics in physiological environments.