Hello, A yearly allocation for the LCRC cluster has been requested with the following updated information: Submitter/PI: Benoit Roux 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 Be 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: Detailed understanding of the fundamental physical forces driving the structure and dynamics of proteins and membranes is essential for the engineering of these biologically key molecules for commercial and medical purposes. Towards such understanding, theoretical studies of proteins and lipids based on empirical force fields (FF) have made important contributions. To further these efforts, improvements in FF accuracy based on extensions of the underlying energy function are required, including the explicit inclusion of induced electronic polarizability. In the proposed study we will investigate the fundamental forces driving a range of phenomena in both proteins and lipids using the computationally efficient polarizable FF based on the classical Drude oscillator, allowing for unbiased simulations on the microsecond time scale as well as simulations exploiting a range of enhanced sampling technologies. Investigations will focus on how the explicit treatm ent of electronic polarization underlies a range of experimental observables. These efforts will yield a better understanding of the fundamental forces driving the structure and dynamics of biomolecular systems while also helping to validate the current generation of the Drude FF. Results from these studies will guide efforts aimed at further improving the model for proteins, lipids, metal ions, and drug-like molecules. We have made significant progress towards improvements in the CHARMM36 additive protein and lipid FF, development of methods to facilitate FF optimization, and the 1st generation Drude polarizable FF for atomic ions, proteins and the lipid DPPC. We have subsequently used these models in large-scale simulations, demonstrating quantitative agreement with experimental data associated with the improved model of the fundamental forces due to the explicit treatment of electronic polarizability. Preliminary results already show that new physical mechanisms emerge when explicitly accounting for induced polarization. In the near future we will extend these efforts, focusing on selected peptides and proteins, selected membranes and membrane-protein interactions and on ligand-protein interactions including ions and drug-like molecules. Specific improvements will be made in the intra- and intermolecular electrostatic and Lennard-Jones (LJ) terms, the treatment of non-bonded interactions between different classes of functional groups not specifically targeted until now, and the extension of the energy function to include charge transfer between selected moieties in the FF. To use FF methods it is necessary to automatically generate parameters for a wide range of chemical entities of interest at a level of accuracy required for reliable predictions. Our previous experience towards this goal with the development of the General Automated Atomic Model Parametrization (GAAMP) web server (see http://gaamp.lcrc.anl.gov) is encouraging. GAAMP was used to optimize electrostatic parameters for 217 molecules within the polarizable Drude model, with the resulting model yielding a R2 with respect to experiment of 0.87 and an AUE of 0.92 kcal/mol. These results compare to values of R2=0.90 and AUE=0.85 for GAFF/AM1-BCC model despite that GAFF-adapted LJ parameters were used rather than LJ parameters optimized specifically for the Drude electrostatic model. To improve the treatment of ligands and drug-like molecules we will extend and optimize the Drude LJ parameters. Work will involve the implementation of a systematic atom typing algorithm together with t he development of new LJ parameters targeting neat liquid properties and relative interaction energies from high level QM calculations, expanding on methods developed in the MacKerell laboratory. Utilities such as the GAAMP will be extended for the automated optimization of Drude parameters for drug-like molecules in anticipation of the application of the Drude model in the area of drug discovery. These efforts will lay the groundwork for a readily extendible Drude FF for drug-like molecules, that will be put into an engine similar to that in place for the additive small molecule CGenFF. Specifically, in the coming year we will work on: 1. Fundamental forces at play in membranes and membrane-protein interactions. Investigations will focus on the impact of polarization of the nonpolar hydrocarbon core and the internal dielectric structure of membranes on the reproduction of experimental data including 2D-IR spectroscopy, solution and solid state NMR, scattering, ion binding to charged lipids, permeation of small species and cell penetrating peptides, and voltage-sensitive membrane-bound chromophores. Results will be used to drive additional lipid FF optimization, and will include extension to unsaturated and anionic lipids, cholesterol and sphingomyelin. 2. Fundamental forces at play in ligand binding. The impact of polarization on the binding of ions and ligand to proteins will be investigated. The allosteric regulation of thrombin by Na+ binding will be elucidated. The fundamental forces governing the binding of charged ligands to cytochrome c peroxidase and the acetylcholine-binding protein (AChBP) will be investigated. An automated parameter optimization approach will be extended and applied to a collection of model compounds with broad chemical functionalities representative of drug molecules, yielding an engine that will allow for the objective generation of topologies and parameters for drug-like compounds that will be compatible with the remainder of the Drude FF. 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. The work will yield novel insights on the fundamental contribution of electronic polarization to biological phenomena such as peptide folding, membrane permeation and ligand-protein interactions. This work will allow us to validate and improve the accuracy of the Drude FF, which is currently the **only** polarizable FF that allows for computationally efficient MD simulations on the microsecond time scale for large biomolecular systems. An allocation from LCRC of the Argonne National Lab is therefore requested to accomplish this project. Industry partnership: Project URL: http://thallium.bsd.uchicago.edu/RouxLab/ 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 (in GAAMP) to compute energies from sets 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