Hello, A new project on the LCRC cluster has been requested. Please forward the information on to the LCRC Allocation sub-committee. Applicant's name: Maksym Kryvohuz Applicant's institution: ANL Applicant's division: CSE Project Name: Quantum_catalysis Project title: Quantum effects in enzyme catalysis Associated funding: Director’s Fellowship Other Systems: None Science: The objective of this project is to perform modeling of hydrogen transfer step in several enzyme-catalyzed reactions, in which significant nuclear quantum effects were experimentally observed. The origin of high efficiency of enzymes as catalysts remains unclear, yet fundamental understanding of the mechanisms underlying the function of enzymes would assist in the design of bio-inspired synthetic catalysts. It has been suggested that nuclear quantum effects such as tunneling of hydrogen through the reaction barrier can contribute to the efficiency of enzymatic catalysis, yet its role in catalysis is unclear. In this project, a multi-dimensional quantum modeling of the rate-limiting proton transfer step catalyzed by methylamine dehydrogenase (MADH) will be performed and its rate as well as primary kinetic isotope effect will be calculated. It has been estimated that 99% of this reaction occurs by tunneling at physiological temperatures. The role of dy namical effects of enzyme vibrations on the proton-transfer step as well as nuclear quantum effects such as multidimensional tunneling will be analyzed at the ab initio level. The results of this project will provide novel understanding of the role of quantum effects in enzyme catalysis and suggest ways to improve catalytic efficiency of bio-inspired synthetic catalysts. The proposed project supports Argonne’s M2D2 initiative of synthesis by design as well as on development of biomimetic catalysts for efficient conversion of biomass into fuels. Project description: Quantum effects of H-transfer step in enzyme catalyzed reactions will be studied via the instanton reaction rate theory [J.Chem.Phys. v.134, p.114103 (2011)] which allows one to rigorously incorporate nuclear quantum effects in multiple dimensions with on-the-fly computations of accurate electronic reactive potential energy surface (PES). An efficient code for parallel computations of reaction rates and PES has been developed and successfully applied to describe quantum kinetics of H-transfer reactions in 13 and 23-atomic systems. In the present project H-transfer reactions in enzymes will be studied using the same technique. For this purpose, from 40 to 80 atoms of the active site of MADH enzyme will be treated quantum mechanically with electronic structure calculations of reactive PES performed in Gaussian 09 package. The remaining 7250-7200 atoms of MADH as well as 3000-4000 atoms of solvent will be treated classically with molecular mechanics for ce field. The numerical algorithm is based on determination of tunneling trajectories under the multidimensional reaction barrier by optimization. The tunneling trajectory is divided in 16 points and its optimal shape is determined by variational principle together with on-the-fly calculations of PES at these 16 points. One round of optimization requires about 10 iterations, which results in the total number of 16*10=160 single-point electronic structure calculations (with frequency analysis, i.e., computation of matrix of second derivatives which is essential for the process of optimization) to find an optimized tunneling path at a single temperature. Tunneling trajectories at several temperatures (from 5 to 6 different values) need to be determined to obtain Arrhenius plot, which requires (160 configurations)*(5 temperatures)= 800-1000 single point electronic structure calculations for a system of 40-80 atoms. Averaging over about 40 configurations of enzyme/solvent enviro nment is necessary to get an average value of a canonical reaction rate constant. Thus (1000 single point calculations)*(40 environment configurations) = 40000 single-point computations (with frequency analyses) constitute the minimum number of computations required for one enzyme system. DFT mPW1K or B3LYP methods will be used for on-the-fly electronic structure calculations of PES. Numerical tests shown below indicate that an organic system of 45 atoms requires about 24 core-hours for a single job with frequency analysis. The estimated number of computer time for the project is therefore (24 core-hours)*(40000 computations) = 960,000 core-hours. Number of people to run the above simulations: 1. Project URL: Requested allocation: 960000 Q1: 240000 Q2: 240000 Q3: 240000 Q4: 240000 Justification: A test of performance of B3LYP and mPW1K methods with 6-31+G(d,p) basis for a frequency analysis of a fixed geometry 45-atom organic molecule (PAF-1 monomer), which contains 20 atoms of H and 25 atoms of C was performed with Gaussian 09 code using 8, 16, 24, and 32 cores. The performance results are summarized in the table below. Substantial speed-up is achieved with the increase in the number of cores. Nodes x Cores Wall Time (min) B3LYP mPW1K 1 x 8 159 172 2 x 8 82 91 3 x 8 58 62 4 x 8 45 49 The requester has used undetermined amount hours of their initial startup project. In addition to approving an initial amount, please specify a Category and Subcategory for this project. For a list of the current selection of approved categories, please see: https://wiki.lcrc.anl.gov/wiki/Processes/Categories Once the Allocation committee has approved the project, please go to the Project Management page to create it: https://accounts.lcrc.anl.gov/projects.php Thank You, The LCRC Accounts System