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Role of Flexibility and Polarity as Determinants of the Hydration of Internal Cavities and Pockets in Proteins

Ana Damjanovi ^* , Jamie L. Schlessman , Carolyn A. Fitch ^*, Angel E. García  and Bertrand García-Moreno E. ^*

^* Johns Hopkins University, Department of Biophysics, Baltimore, Maryland; U.S. Naval Academy, Chemistry Department, Annapolis, Maryland; Rensselaer Polytechnic Institute, Department of Physics, Applied Physics and Astronomy and Center for Biotechnology and Interdisciplinary Studies, Troy, New York; and Laboratory of Computational Biology, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, Maryland

Correspondence: Address reprint requests to A. Damjanovi, E-mail: adamjan1{at}jhu.edu; or B. García-Moreno E., E-mail: bertrand{at}jhu.edu.

Molecular dynamics simulations of Staphylococcal nuclease and of 10 variants with internal polar or ionizable groups were performed to investigate systematically the molecular determinants of hydration of internal cavities and pockets in proteins. In contrast to apolar cavities in rigid carbon structures, such as nanotubes or buckeyballs, internal cavities in proteins that are large enough to house a few water molecules will most likely be dehydrated unless they contain a source of polarity. The water content in the protein interior can be modulated by the flexibility of protein elements that interact with water, which can impart positional disorder to water molecules, or bias the pattern of internal hydration that is stabilized. This might explain differences in the patterns of hydration observed in crystal structures obtained at cryogenic and room temperature conditions. The ability of molecular dynamics simulations to determine the most likely sites of water binding in internal pockets and cavities depends on its efficiency in sampling the hydration of internal sites and alternative protein and water conformations. This can be enhanced significantly by performing multiple molecular dynamics simulations as well as simulations started from different initial hydration states.

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