Conformational Ensembles from Experimental Data and Computer Simulations

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Conformational Ensembles from Experimental Data
and Computer Simulations Sunday Speaker Abstracts
21
Comparison of the Global Dynamics of Proteins as Assessed by WAXS and MD
Hao Zhou2, Hugo Guterres3, Carla Mattos3, Lee Makowski1,3.
1Northeastern University, Boston, MA, USA, 2 Northeastern University, Boston, MA, USA,
3Northeastern 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
No Abstract