SBIR-STTR Award

New opportunities are available to take advantage of the many recent advances from the areas of density functional theory (DFT) development, advances in quantum mechanical (QM) algorithms for DFT on isolated molecules, and combine them into next generation advanced condensed phase sim- ulation approaches for more accurate description of transition state energetics for enzymatic mech- anisms, improved lead optimization in drug design, better descriptions of docked protein-protein interactions, and higher quality back-calculation of biomolecular NMR observables. Proposed project seeks to make signi?cant progress in this area by combining the use of accurate new density functionals with periodic boundary conditions and new extended Lagrangian schemes that greatly reduce computational cost and thus increase ab initio molecular dynamics timescales. Benchmark calculations on periodic systems including molecular crystals and on aqueous zwitterionic peptides will be performed.

Project Terms:
Algorithms; aqueous; Area; Back; base; Benchmarking; Biochemical Process; Biological; biological systems; Biomolecular Nuclear Magnetic Resonance; biophysical techniques; chemical reaction; Code; complex biological systems; Computer Simulation; Computer software; Computing Methodologies; cost; Coupled; Covalent Interaction; Crystallization; density; Development; Differential Equation; Docking; Drug Design; electronic structure; Enzymes; Evaluation; Freedom; Generations; Glycine; Hybrids; improved; large scale simulation; lead optimization; Libraries; Liquid substance; macromolecule; Mechanics; Methods; Modeling; Molecular; molecular dynamics; molecular mechanics; next generation; novel; Peptides; Periodicity; Pharmaceutical Preparations; Phase; Polymorph; programs; protein protein interaction; Proteins; prototype; quantum; Research; Scheme; simulation; small molecule; software development; Spectrum Analysis; stem; System; theories; Time; tool;

Next Generation Methods for Advanced Condensed Phase Simulations in Q-Chem Biophysical systems exist in the condensed phase, and that is the environment in which their properties should be computer-modeled. The correct theory to describe the electrons is using ab initio (AI) quantum mechanics (QM), whilst nuclear motion requires molecular dynamics (MD). The combination, AIMD, is thus the appropriate tool for biophysical simulations. While use of AIMD is vastly more expensive than MD with empirical potentials, it is nonetheless the standard to aspire to. AIMD enables correct treatment of bond-breaking for reactive processes, as well an accurate description of the non-bonded interactions that determine solvation and conformational preferences. This Phase II proposal has the objective of bringing a production level AIMD code to the Q-Chem software package. The key justi?cation for the proposed work, and the potential value of the resulting product is that it will bring together capabilities that are not found jointly in any other AIMD code. The valuable synergy between the density functional theory implementation for periodic boundary conditions (DFT-PBC), and advanced algorithms for ef?ciently and accurate propagating the MD is the core innovation of this project. With regard to DFT-PBC (the ?rst speci?c aim), the focus is on implementing high precision, high ef?ciency algorithms for the critical components of DFT with advanced functionals. Our code will support the latest meta-generalized gradient approximations (mGGAs), with inclusion of non-local van der Waals density functionals, that are not available in DFT-PBC codes to date. We will addition- ally provide support for range-separated exact exchange, with high ef?ciency. These capabilities will come with energies and gradients. Our software framework can also permit all-electron calculations as needed e.g. for NMR properties that depend on the electron density at the nucleus. Our modular code will support ef?cient on-node parallelism. To propagate MD ef?ciently and stably (the second speci?c aim), we employ two innovative statis- tical mechanics (SM) algorithms that have been proven in conventional MD, but are not yet available in any production AIMD code. First, we are extending the inertial extended Lagrangian self-consistent ?eld (iEL/SCF) method to work robustly and ef?ciently with AIMD, building upon promising Phase I results, by combining it with a stochastic-isokinetic integration (SII) scheme to enable a single but larger MD time step. Second, we will explore the combination of iEL/SCF-SII with a multiple time- stepping method in which will explore whether different components of the QM force can be updated on different timescales in the AIMD. In ?nal Aim 3 we test the combined DFT-PBC and iEL/SCF-SII capabilities on biophysical appli- cations including zwitterionic glycine and valine peptides in aqueous solution and molecular crystals. 1

Public Health Relevance Statement:
PROJECT NARRATIVE Next Generation Methods for Advanced Condensed Phase Simulations in Q-Chem This project will provide improved computer-based quantum mechanical modeling of biophysical problems in the condensed phase, by synergistic combination of periodic boundary conditions with advanced molecular dynamics methods. The resulting capability will be valuable for applications such as the role of solution on conformational energies, on binding and reactions at active centers, and for validating more approximate simulation methods. 1

Project Terms:
Algorithms; Ally; aqueous; Area; base; Benchmarking; Binding; Biological; biophysical model; biophysical tools; Biophysics; Cell Nucleus; Code; complex biological systems; computational chemistry; Computer Assisted; Computer Models; Computer software; Computers; Computing Methodologies; cost; Crystallization; density; Drug Design; electron density; electronic structure; Electrons; Environment; Enzymes; Evaluation; flexibility; Free Energy; Generations; Glycine; Hybrids; improved; Industry; innovation; Isotonic Exercise; lead optimization; Letters; Libraries; Liquid substance; Mechanics; Methodology; Methods; Modeling; Modernization; Molecular; Molecular Conformation; molecular dynamics; Motion; next generation; novel; Nuclear; Peptides; Periodicity; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Polymorph; preference; Process; Production; professor; programs; Property; Proteins; prototype; quantum; Quantum Mechanics; Reaction; Research; Role; Scheme; Science; Scientist; simulation; simulation software; small molecule; Software Framework; software infrastructure; Spectrum Analysis; Statistical Mechanics; stem; synergism; System; Technology; Testing; theories; Time; tool; Update; Valine; Work