This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Molecular mechanics (MM) are the key component in the armamentarium used by computational chemists and biologists to study molecular structures and energies for both organic and biological molecules. Force field that describes the energy of a system with bond stretching, bond angle bending and torsional angle twisting etc, is the cornerstone of a MM model. Most the widely used force fields, including AMBER, CHARMM, MMFF, MM3, are developed to study a specific class of molecules, either biological or organic molecules. The purpose of this project is to develop a general force field that works well for both biological and organic molecules. A universal, self consistent and well parameterized force field is essential to perform structure-based drug design. The AMBER force fields (parm94, parm99, parm99SB, parm02) was originally developed for protein and nucleic acids. The fact that AMBER has only limited parameters for organic molecules has prevented it from being widely used in drug design. Recently, we put some effort to extend AMBER to cover the chemical space of organic molecules that are made up of H, C, N, O, S, P, F, Cl, Br, I. A paper on this general AMBER force field has been published (J. Comput. Chem., 25, 1157-1174, 2004). To further improve GAFF and extend this general force field to cover more chemical spaces that include metallic elements, we plan to (1) perform ab initio optimizations for up to 40,000 organic molecules to derive bond length and bond angle equilibrium parameters;(2) carry out ab initio torsional angle scanning to derive the force constants for the missing torsional parameters;(3) do frequency analysis for up to 5000 organic molecules to further improve the force constants of bond stretching, bond angle bending as well as torsional angle twisting;(4) investigate different function forms of modeling metallic bond angles that typically have more than one equilibrium bond angles (such as 90 and 180 degrees in octahedral configuration), do Steps (1) to (3) for metallic model compounds selected from CSD (Crystal Structure Database) and the truncated protein-metal, DNA-metal systems;(5) develop a polarizable version of GAFF to be used in combination with polarizable protein/nucleic acid force fields;(6) develop an efficient charge model that mimic the HF/6-31G(d) ESP charges using the Gasteigers scheme. With those improvements, we are confident that the second version of GAFF will be a significantly better universal force field for drug design. Many of the planned calculations have been done;however, we need more computer resource to achieve the goals. According to our Amber force fields development road map,the second generation GAFF and the first version of polarizable GAFF will be released in Year 2009. We also plan to develop a software package (an improved version of parmscan) to facilitate the procedure of force field parameterization and this package will be put in public domain for free download.
Showing the most recent 10 out of 292 publications
