FRG: Metalloproteins: Computational Challenges, Methods, and Tools

North Carolina State University, Raleigh NC

Investigators

Abstract

TECHNICAL SUMMARY: The Division of Materials Research and the Office of Cyberinfrastructure contribute funds to support this work. This award to an interdisciplinary focused research group supports computational research and education to investigate key issues related to the structure and function of selected metalloprotiens. As this of necessity involves a multi-method approach, the group will develop a set of computational tools for large-scale biomolecular simulations as part of its program. The research team will build on the achievements under prior NSF support through an award made on a proposal to the Information Technology Research solicitation. Some achievements include: the development of the highly parallel Particle Mesh Ewald Molecular Dynamics, PMEMD, code currently incorporated into AMBER; a fast implementation of higher-order electrostatic multipoles that is the basis of an efficient coding of the AMOEBA force fields in AMBER; a new partitioning of the molecular electrostatic potential; the development of pfaffian wavefunctions for quantum Monte Carlo simulations; the coupling of ab initio molecular dynamics; and the establishment of the new quantum Monte Carlo open source package QWalk. The team will focus on investigating: (i) signal transduction Ras proteins; (ii) Vitamin K-dependent coagulation proteins; (iii) select DNA repair enzymes, and (iv) the folding/unfolding of metallopeptides and metalloprotein domains. Methods development thrusts include: (i) new quantum Monte Carlo /molecular dynamics methods and new types of variational wave functions based on pairings and pfaffians, which allow for accurate treatment of quantum processes with complicated multi-reference correlations; (ii) the accurate description of electrostatics for the classical region based on Gaussian basis sets and distributed multipoles; (iii) further development of quantum mechanics and molecular mechanics interfaces; and (iv) developing new free-energy methods based on adaptively biasing potentials. The developed methods will be incorporated into the above packages and tested on multiple architectures including the new generation of petaflop machines. This award supports continuing curricula development in computational methods and science at the Center for High Performance Simulation, which was founded at NC State as part of the previous funding cycle. The group will also develop a new undergraduate Computational Physics course. NON-TECHNICAL SUMMARY: The Division of Materials Research and the Office of Cyberinfrastructure contribute funds to support this work. This award to an interdisciplinary focused research group supports computational research and education to investigate key issues related to the structure and function of selected protiens that consist of a metal atom or cluster bound to a group of proteins that are held together by protein-protein interactions. In the process, the team will develop a set of computational tools for large-scale computer simulations of large molecules that occur in living systems. Reliable computer simulations of large complicated molecules are extremely challenging. The team will focus on metalloproteins and metalloenzymes ? which consist of a metal atom or cluster of atoms bound to a group of proteins that are held together by protein-interactions. The metal atom controls the shape of the molecule and so its biological function. It may also enable particular biochemical reactions without directly participating in them. These are an important class of proteins in life?s processes. Their malfunction is the root cause of many fatal diseases. The team will develop computer simulation techniques that will capture physical phenomena that dominate on different length scales to make the complicated simulations to understand their role in various processes important to life, for example how proteins are synthesized and how DNA is repaired. The resulting cybertools will be made available to the broader scientific community through well known suites of cybertools. This award supports continuing curricula development in computational methods and science at the Center for High Performance Simulation, which was founded at NC State as part of the previous funding cycle. The group will also develop a new undergraduate Computational Physics course.