Conformational Ensembles from Experimental Data and Computer Simulations

Conformational Ensembles from Experimental Data and Computer Simulations

Sunday Speaker Abstracts

Comparison of the Global Dynamics of Proteins as Assessed by WAXS and MD Hao Zhou 2 , Hugo Guterres 3 , Carla Mattos 3 , Lee Makowski 1,3 . 1 Northeastern University, Boston, MA, USA, 2 Northeastern University, Boston, MA, USA, 3 Northeastern University, Boston, MA, USA. Wide-angle x-ray solution scattering (WAXS) is highly sensitive to changes in protein dynamics. Comparison of observed scattering with that predicted for a rigid protein provides information about the spatial extent of interatomic distance fluctuations. This information is quantitated as the standard deviation of interatomic distance as a function of interatomic distance. Referred to here as a sigma-r plot, this metric can be estimated from WAXS and from molecular dynamics (MD) trajectories. Comparison of sigma-r plots from WAXS and MD can assess the degree to which an MD simulation represents a structural ensemble. It also makes possible demonstration of the self-consistency of dynamic behavior as assessed by experimental and computational approaches. Where comparison reveals inconsistencies it may provide clues to their origin: They may be caused by errors in the model for the solution structure of the protein; inaccuracies of computated trajectories; or impact of experimental conditions on the structure and/or dynamics of the protein. We demonstrate the power of this approach by analysis of WAXS data from several proteins including HIV protease and three isoforms of ras. We show that the observed structural fluctuations of HIV protease are of greater extent than exhibited in 100 nsec MD simulations, suggesting that the MD trajectories are of inadequate length to fully explore the solution ensemble. Joint computational and experimental studies of H-ras and K-ras demonstrate extraordinary consistency between calculated and observed estimates of protein dynamics, validating the accelerated MD studies of these molecules. By contrast, inconsistencies between calculated and observed estimates of dynamics in N-ras suggest that the crystal structure of N-ras may not be an adequate representation of its solution structure. These examples demonstrate the power of the sigma-r plot for assessment of global dynamics of proteins.

Bayesian Modeling with Ensemble Data

Michael Habeck Max Planck Institute for Biophysical Chemistry, Göttingen, Germany

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