Towards Quantitative Structure and Dynamics of Biological Macromolecules Using Classical Molecular Dynamics Simulations and Neutron Scattering Spectroscopy

Joseph E. Curtis, NCNR

The use of molecular dynamics (MD) simulations in the study of biological systems is becoming a ubiquitous tool that is being used in a large variety of research problems. Although the use of MD simulations is increasing at a rapid rate there still exists a need to develop and test simulation methodologies for a number of non-native condensed phase environments. In the future it will be possible to validate at the atomic level the validity of force-fields and methodologies by neutron scattering and nuclear magnetic resonance spectroscopy. The validation of simulation methods by comparison to neutron scattering spectra over relevant time and length scales is essential to advance MD methodologies.

Examples of the application of MD simulations to a variety of collaborative research projects will be presented. Specifically, we have studied the hydration and temperature dependence of the dynamics of various proteins and nucleic acids by MD simulations and neutron scattering spectroscopy. We have discovered and characterized onsets of anharmonic dynamics as a function of temperature. We have identified that the dynamics of non-exchangeable hydrogen atoms on methyl groups are distinctly different than hydrogen atoms covalently bonded to other heavy atoms. Methyl protons can potentially be used as a site-specific probe of the local conformation of proteins in the amorphous phase.

In addition, we have developed and validated MD simulation methods to simulate proteins encased in polyols and various unary and binary carbohydrate amorphous glasses. The ability to simulate proteins in these pharmaceutically relevant conditions is important to determine the atomistic factors that govern the stability of proteins in the amorphous phase. By carefully validating our methods against available neutron and light scattering data we are able to conclude that a major factor that stabilizes proteins in glasses is the inertia of the glass matrix rather than specific protein-solvent interactions.

And finally, recent results on the development of conformational sampling tools to aid in the design and analysis of small angle scattering experiments will be presented. We have used these tools to predict a set of structures for the HIV-1 Gag protein under high salt conditions. These tools, once mature, may be useful in the study of intrinsically disordered proteins and the elucidation of macromolecular interactions in solution.

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