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.

Project Report

Reliable biomolecular simulations are extremely challenging, because they involve large, complex macromolecules bathed in a solvent environment, long-range electrostatic interactions, correlation effects, bond breakage, competing many-body phenomena, and a high sensitivity to both temperature and dynamical effects. Among the different classes of biomolecules, the study of metalloproteins and metalloenzymes ­–which typically consist of a metal atom or cluster bound to a protein complex– is particularly challenging. Typically, the metal atoms play a crucial role in either stabilizing the protein conformation or enabling the protein to carry out its catalytic function. The aim of our proposal has been to investigate key issues as related to the structure and function of selected metalloprotein systems. In addition, the proposal also set out to further enhance the computational tools available to simulate such biomolecular systems. In terms of the slected metalloprotein systems, work concentrated on the action of vitamin K-dependent coagulation proteins, DNA repair enzymes, Zn-porphyrin systems, and other heavy-metal systems. For the vitamin K-dependent coagulation proteins, we investigated the folding processes of the gamma-carboxyl glutamic acid domains of these proteins (these play a crucial role in the blood coagulation cascade). As a result, we have been able to develop a model that describes in atomic detail the production of thrombin, which is central for blood coagulation. The model is consistent with experimental mutation studies, and sheds light on the action of prothrombin and the peptide cleavages that must occur. Turning to DNA repair enzymes, we conducted QM/MM calculations on the DNA repair enzyme beta polymerase, with a focus on identifying and characterizing the catalytic site, which involves two metal ions combined with oxygen ligands. Aside from investigating this specific enzyme, an experimentally accessible mutation of the enzyme was also studied. Consistent with experimental results, this mutation is characterized by a higher activation energy and therefore decreased DNA repair activity. The metal organic systems investigated included Zn-porphyrin systems, small manganese oxide systems, vanadium-benzene systems, and work on predicting the pKas of metal ions. As an additional product of our investigations, we were able to characterize the structure and free energies of polyproline peptides, investigate a rare secondary structure termed alpha-sheet, and gain important insights into the aggregation phenomena associated with polyglutamine diseases. There have also been several important methodological outcomes associated with this proposal. These have focused on developing and characterizing tools for Quantum Monte Carlo simulations (which we use for the accurate treatment of metal ions) and the larger-scale classical molecular dynamics simulations. In terms of the former, we added to QWALK, which is an Open Source Quantum Monte Carlo code developed by our group for large-scale calculations of both molecular and solid systems. Other developments included the study of spin-systems, correlated trial wavefunctions, and the development of effective core pseudopotentials for Quantum Monte Carlo simulations. In terms of classical molecular dynamic simulations, we focused on further developing the Adaptively Biased Molecular Dynamics (ABMD) method for accurate free energy calculations, new enhanced sampling methodology, methods for probing transition rates with Steered Molecular Dynamics simulations, and enhancing the development of continuous electrostatics for accurate biomolecular simulations. Some of the relevant code have been released to the general public via the AMBER simulation package.

Agency
National Science Foundation (NSF)
Institute
Division of Materials Research (DMR)
Application #
0804549
Program Officer
Daryl W. Hess
Project Start
Project End
Budget Start
2008-09-15
Budget End
2012-08-31
Support Year
Fiscal Year
2008
Total Cost
$1,470,000
Indirect Cost
Name
North Carolina State University Raleigh
Department
Type
DUNS #
City
Raleigh
State
NC
Country
United States
Zip Code
27695