FY2010 - Oak Ridge National Laboratory

Director’s R&D Fund—
Neutron Sciences
water model in protein simulations without a loss of accuracy in interpreting neutron experiments may be
possible.
Information Shared
Glass, D., M. Krishnan, D. Nutt, and J. C. Smith. 2010. “Temperature Dependence of Protein Dynamics
Simulated With Three Different Water Models.” J. Chem. Theory Comput.6(4), 1390–1400.
Krishnan, M., and J. C. Smith. 2009. “Response of Small-Scale, Methyl Rotors to Protein-Ligand
Association : A Simulation Analysis of Calmodulin-Peptide Binding.” J. Am. Chem. Soc.
131(29),10083–10091.
Neusuis, T., I. M. Sokolov, and J. C. Smith. 2009. “Subdiffusion in time-averaged, confined random
walks.” Phys. Rev. E 80, 011109.
05839
Motional Changes in Biomolecular Complexation
Jeremy C. Smith
Project Description
The research is directed at understanding the dynamical changes on complexation in biological systems
by combining computer simulation with experiments on the next-generation Spallation Neutron Source
(SNS) at ORNL. Inelastic scattering experiments on ligand binding will be interpreted using analytical
modeling and normal mode analysis, together with calculations on methyl group dynamical perturbations.
Spin echo spectroscopic experiments will be performed on ligand-perturbed slow domain motions and
corresponding software developed to interpret the experiments with molecular dynamics simulation.
Mission Relevance
Recent DOE press releases, reports, R&D and budget priorities indicate that this project is well aligned
with DOE’s neutron scattering research focus for the next 5 years. The present project will begin to
address the roadblocks to improving our understanding of the use of computer simulation in the analysis
of neutron scattering with computer simulation.
Results and Accomplishments
Ligand binding has been is characterized using a simple analytical “ball-and-spring” model and all-atom
normal mode analysis of the binding of the cancer drug methotrexate (MTX) to its target, dihydrofolate
reductase (DHFR). The analytical model predicts that the coupling between protein vibrations and ligand
external motion generates entropy-rich, low-frequency vibrations in the complex, a result in qualitative
agreement with the neutron scattering experiment. Also solid foundation has been established for the
interpretation of inelastic and spin echo spectroscopy from globular protein complexes.
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