DYNAMICAL SIMULATIONS OF KINKED DNA AND CRYSTALLOGRAPHIC REFINEMENT BY SIMULATE

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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. Keywords: Molecular Dynamics, Monte Carlo, Weighted Histograms, constant pH simulation, pKa calculation Abstract: It is necessary to properly treat titratable groups, such as acidic or basic amino acid residues, during the course of a molecular dynamics simulation, especially since fluctuations in titration states are expected to be correlated with other configurational parameters. This is especially challenging in macromolecular complexes such as protein-DNA complexes, where many titratable and/or charged groups are a significant distance from bulk solvent. We are developing a hybrid Molecular Dynamics/Monte Carlo-Multiple Histogram (MD/MC-WHAM) method for constant pH simulations and pKa calculations. A summary of the features of our combined MC/MC-WHAM approach is as follows: 1) Explicit solvent is used, improving the electrostatic modeling. The simulation force field is based on the microscopic Amber8 Force Field(1,2), which includes Ewald long-range electrostatics, and optional polarizability 2) Each titratable site is modeled in detail with discrete microstates. 3) One simulation cycle consists of an MD sub-cycle and an MC sub-cycle. The MD enforces constant N,P,T and the MC enforces constant pH. Together both sub-cycles model a true biochemical ensemble, constant N,P,T and pH. This facilitates modeling of correlations between the titration states at multiple sites as well as between titration states and configuration states. 4) WHAM(5,6) histogram methods facilitate the calculation of a full range of thermodynamic parameters, including titration curves and pKa values. This proposal is for the next stages of development, which are to: 1) Complete determination of the force field correction number for Cystine 2) Determine statistical requirements (# of snapshots) for given levels of precision 3) Investigate system with two titratable sites to verify that appropriate interactions are being simulated 4) Determine the correction term for a second amino acid side chain (Glutamic acid)