Hello, A yearly allocation for the LCRC cluster has been requested with the following updated information: Submitter/PI: Benoit Roux Project Name: Drude Division: BIO Project title: Development and validation of new polarizable force field for molecular dynamics Associated funding: LDRD: 2009-047-R1, "Novel Computing Methodologies for the Simulation of Complex Molecular Systems" NIH grant from NIGMS R01-GM072558: Polarizable Force Field For Proteins and Lipids Other Systems: BG/P, NCSA, PSC, KBT Science: The functional form and parameters of a new force field accounting for induced polarization in molecular dynamics simulations must be developed, optimized, and validated for various biomolecular systems. Project description: At the present time, MD simulations are not only limited by the computational resources but also by the physical correctness and accuracy of the underlying atomic models. Without a systematic approach to generate, test and validate the accuracy of the force fields, the value of MD simulations will always remain in question. The development of potential functions for computer simulations has a long history and is still a very active field. Essentially all of the MD simulations of complex molecular systems (biological or not) are currently carried out using fixed-charge non-polarizable force fields, even though there is a broad consensus that electronic polarization effect ought to be included. The important role of polarization is particularly obvious for self-assembling amphiphilic molecules, containing polar or charged groups as well as nonpolar moieties (see below). A number of research groups are working at developing new algorithm to treat polarizati on, either with inducible point dipoles, fluctuating charges, or classical Drude oscillators. The latter approach, which we have adopted, is the most advantageous due to its simplicity and computational efficiency. The goal is to develop, optimize, and validate the functional form and parameters of a new force field accounting for induced polarization in molecular dynamics simulations. We are particularly interested in ion solvation properties. # computational methods The computational method involves ab initio quantum mechanics, as well as classical molecular dynamics simulations and free energy perturbation. The induced polarization is represented by introducing a small auxiliary charged particle attached to the nucleus by a spring. The pair forms a Drude oscillator. It can be shown that this construction accounts properly for the physics of induced polarization in molecular interactions. # scalability issues The new force field is developed to be implementable in a wide range of existing molecular dynamics codes. Currently, the model is supported by CHARMM, and in NAMD. Scalability is typically better with NAMD. But that is for simple brute force simulations. For alchemical free energy perturbation, we can run replica-exchange simulations FEP/REMD using CHARMM/REPD, which is extremely scalable. # computations planned We are now refining ion solvation models in liquid N-methylacetamide (NMA). We also need to study methyl-acetate, which is an imprtant fragment of phospholipid molecules forming membrane bilayers. Those are needed to model biomolecular systems. The work will comprise - high level ab initio on small clusters - FEP for monovalent ions solvation in NMA - FEP divalent ions solvation in NMA - FEP of methylacetate in water # software requirements We use Gaussian, Qchem, CPMD, CHARMM, and NAMD. # sizes of calculations run on and/or planned for Fusion or other systems The work always starts with some ab initio in small clusters. The most demanding part of the project corresponds to the large number of FEP computations needed to fully optimize the force fields. The FEP simulations are extremely scalable via CHARMM/REPD when we carry them as replica-exchange MD. The osmotic pressure require several MD at increasingly high concentrations with large systems. Lastly, we also use CPMD for some systems when required (like we simulated Na+ and K+ in NMA to clarify issues of coordination numbers). # expected number of project members: The number of members is expected to be 5-6, including Benoit Roux, Karen Callahan (ions in ethanol), Yun Luo (osmotic pressure), Chris Rowley (divalent ions), from the University of Chicago. In the coming year we need to parametrize divalent cations solvated in N-methylacetamide. This will require both ab initio calculations as well as solvation free energy computations. Request: The dominant part of the project is the FEP calculations. To estimate the number of SUs, it is sufficient to focus on what is needed for this. For one case, we typically require about 100 trials to scan the space of parameters and search for the optimal model. We have to do five cases (Na+ and K+ in NMA, Ca+2 and Ba+2 in NMA, and methyl-acetate in water). A single solvation FEP/REMD calculation: 75 windows/replica One replica use one node (8 cores). Sampling of 0.1 ns takes 2 hours. Total needed: 75*2*8 = 1,200 core-hours Total needed for one complete parametrization : 120,000 core-hours Total needed for five complete parametrization: 600,000 core-hours. This project is long-term, and the allocation could be evenly divided over each quarter with no problem. RECENT REFERENCES Yu, H; Mazzanti, CL; Whitfield, TW, et al. A Combined Experimental and Theoretical Study of Ion Solvation in Liquid N-Methylacetamide. JOURNAL OF THE AMERICAN CHEMICAL SOCIETY Volume: 132 Issue: 31 Pages: 10847-10856 Published: 2010 Baker, CM; Lopes, PEM; Zhu, X, et al. Accurate Calculation of Hydration Free Energies using Pair-Specific Lennard-Jones Parameters in the CHARMM Drude Polarizable Force Field. JOURNAL OF CHEMICAL THEORY AND COMPUTATION Volume: 6 Issue: 4 Pages: 1181-1198 Published: 2010 Yu, HB; Whitfield, TW; Harder, E, et al. Simulating Monovalent and Divalent Ions in Aqueous Solution Using a Drude Polarizable Force Field. JOURNAL OF CHEMICAL THEORY AND COMPUTATION Volume: 6 Issue: 3 Pages: 774-786 Published: 2010 Project URL: http://thallium.bsd.uchicago.edu/RouxLab/ Current FY Hours Used: undetermined amount New FY Requested allocation: 600000 Q1: 150000 Q2: 150000 Q3: 150000 Q4: 150000 Justification: We have an excellent track record of publication in this field, and we will make good use of the allocated time. The project involves a variety of different computations (MD, ab initio, FEP), which are all very important to develop good models. We will definitely utilize all the allocation requested. Thank You, The LCRC Accounts System