Hello, A yearly allocation for the LCRC cluster has been requested with the following updated information: Submitter/PI: John Blaas Project Name: Drude Division: CNM Project title: Development and validation of new polarizable force field for molecular dynamics Associated funding: LDRD Project Number: 2014-161-N0, "Bridging the Electronic and Atomistic Scales: Force Field Development for Reactive Interfaces from First Principles" (Principal Investigators: Subramanian Sankaranarayanan, Maria Chan, Stephen Gray, Michael Davis, and Benoit Roux). NIH/NIGMS grant R01 GM062342, Computational studies of ion channels" (Principal Investigator: Benoit Roux). NIH/NIGMS grant R01 GM072558, "Polarizable Force Field For Proteins and Lipids" (Principal Investigators: Benoit Roux & Alex MacKerell). Other Systems: BG/P, Anton, Midway (from RCC at UC) Beagle (from CI at UC) 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. We are interested in ions binding to proteins and ion channels. Project description: Ions play indispensable roles in the structures and functions of biologically important molecules, many biological processes are also found to be ion-specific. Thorough interpretations of such ion-specificity require models that accurately treat electrostatic interactions between ions and their biological environments, which often involve polarization effects at different magnitudes. In the past several years, a significant number of studies have been published in scientific journals investigating the ion-protein interactions. A large portion of these molecular dynamics (MD) simulations are based on force fields using simple-point representations for one atoms or even for the entire chemically/physically importation groups, for example, the CHARMM, OPLS, GROMOS, and the AMBER force fields. Limitations are often seen in MD simulations employing these force fields and cannot be improved by further parameterization. Due to their underlying assumption of the fixed interaction-potential function, these models are not capable of reflecting the polarizable nature of atoms and thus failed in the cases when the polarization effects are prominent. The recent Ba2+ block experiments of Piasta and Miller on KcsA published in 2011 provide the best and most quantitative information available regarding the thermodynamic binding site selectivity. The translocation of the Ba2+ toward the extracellular side is prevented when an ion binds to the “external lock-in” site. This external lock-in site, which is in near-equilibrium with the extracellular solution, is highly selective for K+ over Na+. This type of analysis supports a thermodynamic view of selectivity. But interpretation of the experimental results is not straightforward. Piasta and Miller proposed that, when Ba2+ is bound to the site S2 and trying to translocate toward the site S1, the highly selective external lock-in site is the site S1. However, our calculations showed that the proposal of Piasta and Miller is impossible: the site S1 would not be a stable binding position for a monovalent cation when Ba2+ is in site S2. We concluded that the external loc k-in site ought to be the site S0; the site becomes more selective (by ~2.5 kcal/mol) due to the presence of the bound Ba2+ in the site S2. The impetus for project 2.1 is provided by the recent availability of this great data from Piasta and Miller20 and by our own study showing that a multi-ion PMF offers the most rational approach to treat the effect of Ba2+ block. Towards the goal of providing a comprehensive and accurate description for the behaviors of ions interacting with macromolecule, in the next allocation cycle, we will focus on improving polarizable ion force fields based on the classical Drude oscillator models. The Drude polarizable force field has been implemented in the program NAMD. It runs efficiently, at a computational cost comparable to that of non-polarizable force fields (slower only by a factor of about 1.4). This study will provide a systematic protocol by employing a wide range of target data. Besides the conventionally employed benchmarks in parameterization such as the gas-phase ion-small molecular cluster interactions and the experimental measured condensed-phase properties, the proposed study will also incorporate QM binding energy calculations for a wide spectrum of proteins. Specifically, we will improve models for biologically important ions interacting with proteins, including the alkali cation Na+, K+, a lkaline earth metal cations Ca2+, Mg2+, and transition metals Zn2+ and Ba2+. In addition, we hope that the approach employed will help initiating and facilitating a systematical approach for evaluating force field performances, thus allowing scientists resolving the functions and behaviors of ions in biological systems more efficiently and with higher confidence. In the propose study, we will perform MD simulations and QM interaction energy calculations for a large number of ion-binding proteins (10 different proteins for each ion type) and utilize these data as the benchmarks in the parameter optimization process. Allocation on fusion at LCRC of the Argonne National Lab is therefore requested to accomplish this project. Industry partnership: Project URL: Current FY Hours Used: undetermined amount New FY Requested allocation: 2000000 Q1: 500000 Q2: 500000 Q3: 500000 Q4: 500000 Justification: We are mainly using NAMD for molecular dynamics simulations with a polarizable force field based on Drude oscillators. This HPC code is well documented and scales very well on all platforms. We also use Gaussian to compute binding energies of ion to proteins sites from a set of configurations previously generated with classical molecular dynamics. On average the configurations used in Gaussian have 50-100 atoms, so the QM calculations are substantial. While the computations are extensive, Gaussian runs well on fusion and it well optimized. Storage requirements: 1 TB Thank You, The LCRC Accounts System