ITR/AP: Tools and Methods for Multiscale Biomolecular Simulations PI: Celeste Sagui – DMR-0121361

1. ITR/AP: Tools and Methods for Multiscale Biomolecular Simulations PI: Celeste Sagui – DMR-0121361 NC State, UNC, Duke • biomolecular simulations are notoriously difficult because they include long-range electrostatics, chemical reactions, water solvent, etc • ideally, one would like to use quantum mechanical methods • given the very large number of atoms involved in a typical biomolecular simulation (>105), this is usually too costly • aim of this grant is to produce tools to integrate different simulation methods • schematic showing hierarchy of methods to be integrated

2. Improved Electrostatics for Biomolecular Simulations Sagui, Pomorski, Darden, Pedersen and Roland NC State, UNC, and NIEHS DMR-0121361 • greatest loss of accuracy in current classical biomolecular simulations is due to poor treatment of electrostatics • electrostatics is absolutely essential to keep folded DNA and protein structures • new algorithms developed by group enables highly accurate simulations at reasonable computational costs • improved description based on partitioning the molecular electronic cloud by means of a Wannier functions • should lead to new generation of biomolecular simulations ab initio WF result Comparison of molecular electrostatic potential for water dimers outside van der Waals surface

3. Mixed Quantum and Molecular Mechanics Simulations of Sulfuryl Transfer Reaction Catalyzed by Human Estrogen Sulfotransferase P. Lin and L. Pedersen • estrogen is one of the most important hormones found in the human body • it is extremely important that the body regulate estrogen, being able to both turn it on and off • the deactivation of estrogen takes place by means of transfering a sulfate group to the hormone • the details of this important reaction were investigated by means of a mixed quantum and classical molecular dynamics simulation, as shown in the movie • movie shows how the sulfate group gets placed on the estrogen

4. Nitrogenase FeMo Cofactor: central ligand and reactions Motivation • The Nitrogenase enzyme catalyzes the transformation of N2 to NH3 under ambient conditions (Fig. 1), with the active site being the iron-molybdenum cofactor (FeMoco) • Recent structural data by Einsle et al.[1]has shown the presence of new light atom inside the FeMoco cavity (C, N or O suggested). Results • Full structural spin-restricted density functional optimization (Fig. 2) provided estimations of binding energies as Eb(O)<Eb(N)<Eb(C). (1) Ordering of spin states with respect to energy is in accordance with [2]. (2) Arguments based on geometry comparisons and redox potentials favor N as the most probable central ligand. Future plans - identification of the site of nitrogen dimer binding and reaction • carrying out Car-Parrinello and with the breakthrough Continuous Quantum Monte Carlo [3] simulation of the reaction [1] O. Einsle, et al.,Science, 297, 1696 (2002). [2] T. Lovell , et al., JACS, 125, 8377 (2003); I. Dance, Chem. Commun. , 324 (2003); [3] J.C. Grossman and L. Mitas, submitted DMR-0121361