CORE RESEARCH GRANT

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. The objective of this continuing Core Project is the development and testing of a new force field for interaction models of biological molecules which includes the effects of electronic charge polarization. We have explored different means for incorporating electronic polarizability into classical empirical force fields for biological molecules. We have settled on our current direction that encompasses the use of a class of polarizable models based on the quantum mechanical principal of charge equalization, and which utilizes the ideas of fluctuating charge distributions via extended systems techniques from statistical mechanics. These approaches have been fully implemented into the CHARMM1 molecular simulation and modeling package during the current grant period and will continue to be optimized for performance and functionality with other modules within CHARMM during the coming grant period. The primary task to be addressed during the pending grant period is the development of a consistent parameterization of the polarizable force field that is useful for modeling both protein and nucleic acid systems, and is compatible with the current generation CHARMM all hydrogen force fields (the version 22 and 28 force fields). To accomplish these goals, we have assembled the necessary quantum chemical tools, e.g., GAMESS/COSMO2,3 and GAMESS4, for the characterization of the "polarized" and vacuum charge distributions needed in developing polarizability parameters for protein and nucleic acid building blocks. We will use these tools to develop the needed model system parameterizations. Furthermore, we have developed a collaborative relationship with Alex MacKerell, the primary developer of the current generation CHARMM force fields, to ensure that the resulting polarizable force field will be parameterized in a manner consistent with existing force fields that do not include the effects of electronic charge polarization. Our main focus during the pending grant period will be to complete the first generation parameterization of a force field for biomolecular systems and perform testing to begin exploration of the role of electronic charge polarization in modulating interactions in proteins and nucleic acids. We are now poised to complete this parameter development, leading to the first generation of polarizable force fields for biological molecules. We note that this is not anticipated to provide force fields that are (initially) more accurate than existing mean field polarizable force fields (present generation empirical force fields). Instead, we aim to provide the basis for understanding when and where polarizable force fields are important in biology, and to learn how better to treat these situations. We are enthusiastic about the opportunities that such a class of force fields will open up to us. For example, we can anticipate that a deeper understanding of ion selectivity in enzymes and nucleic acid systems will be amenable to first principles investigation with this type of force field.