Lennard-Jones Parameters for B3LYP/CHARMM27 QM/MM Modeling of Nucleic Acid Bases.

Combined quantum mechanics/molecular mechanics (QM/MM) methods allow computations on chemical events in large molecular systems. Here, we have tested the suitability of the standard CHARMM27 forcefield Lennard-Jones van der Waals (vdW) parameters for the treatment of nucleic acid bases in QM/MM calculations at the B3LYP/6-311+G(d,p)-CHARMM27 level. Alternative parameters were also tested by comparing the QM/MM hydrogen bond lengths and interaction energies with full QM [B3LYP/6-311+G(d,p)] results. The optimization of vdW parameters for nucleic acid bases is challenging because of the likelihood of multiple hydrogen bonds between the nucleic acid base and a water molecule. Two sets of optimized atomic vdW parameters for polar hydrogen, carbonyl carbon, and aromatic nitrogen atoms for nucleic acid bases are reported: base-dependent and base-independent. The results indicate that, for QM/MM investigations of nucleic acids, the standard forcefield vdW parameters may not be appropriate for atoms treated by QM. QM/MM interaction energies calculated with standard CHARMM27 parameters are found to be too large, by around 3 kcal/mol. This is because of overestimation of electrostatic interactions. Interaction energies closer to the full QM results are found using the optimized vdW parameters developed here. The optimized vdW parameters [developed by reference to B3LYP/6-311+G(d,p) results] were also tested at the B3LYP/6-31G(d) QM/MM level and were found to be transferable to the lower level. The optimized parameters also model the interaction energies of charged nucleic acid bases and deprotonation energies reasonably well.

[1]  Nathalie Reuter,et al.  Frontier Bonds in QM/MM Methods: A Comparison of Different Approaches , 2000 .

[2]  Jiali Gao,et al.  Computation of Intermolecular Interactions with a Combined Quantum Mechanical and Classical Approach , 1994 .

[3]  M. Peräkylä,et al.  Stabilisation of the transition state of phosphodiester bond cleavage within linear single-stranded oligoribonucleotides. , 2004, Organic & biomolecular chemistry.

[4]  W. L. Jorgensen,et al.  Comparison of simple potential functions for simulating liquid water , 1983 .

[5]  S. Sigurdsson,et al.  Sequence preferences of DNA interstrand cross-linking agents: Importance of minimal DNA structural reorganization in the cross-linking reactions of mechlorethamine, cisplatin and mitomycin C , 1991 .

[6]  Influence of adjacent bases on the stacking-unstacking process of single-stranded oligonucleotides. , 1998, Biopolymers.

[7]  Lars Ridder,et al.  Ab initio QM/MM modeling of the hydroxylation step in p-hydroxybenzoate hydroxylase , 2003 .

[8]  Alexander D. MacKerell.  Chapter 7 Empirical Force Fields for Proteins: Current Status and Future Directions , 2005 .

[9]  K M Merz,et al.  New developments in applying quantum mechanics to proteins. , 2001, Current opinion in structural biology.

[10]  P Hobza,et al.  Structure, energetics, and dynamics of the nucleic Acid base pairs: nonempirical ab initio calculations. , 1999, Chemical reviews.

[11]  J. Gready,et al.  Coupled semiempirical molecular orbital and molecular mechanics model (QM/MM) for organic molecules in aqueous solution , 1997, J. Comput. Chem..

[12]  U. Singh,et al.  A combined ab initio quantum mechanical and molecular mechanical method for carrying out simulations on complex molecular systems: Applications to the CH3Cl + Cl− exchange reaction and gas phase protonation of polyethers , 1986 .

[13]  M. Levitt,et al.  Theoretical studies of enzymic reactions: dielectric, electrostatic and steric stabilization of the carbonium ion in the reaction of lysozyme. , 1976, Journal of molecular biology.

[14]  Qiang Cui,et al.  Importance of van der Waals Interactions in QM/MM Simulations. , 2004, The journal of physical chemistry. B.

[15]  A. Elcock,et al.  COMBINED QUANTUM AND MOLECULAR MECHANICAL STUDY OF DNA CROSS-LINKING BY NITROUS ACID , 1995 .

[16]  R. Kierzek.  Nonenzymatic hydrolysis of oligoribonucleotides. , 1992, Nucleic acids research.

[17]  T. Cech,et al.  In vitro splicing of the ribosomal RNA precursor of tetrahymena: Involvement of a guanosine nucleotide in the excision of the intervening sequence , 1981, Cell.

[18]  M. Field,et al.  A Generalized Hybrid Orbital (GHO) Method for the Treatment of Boundary Atoms in Combined QM/MM Calculations , 1998 .

[19]  Adrian J. Mulholland,et al.  Ab initio QM/MM study of the citrate synthase mechanism. A low-barrier hydrogen bond is not involved , 2000 .

[20]  György G. Ferenczy,et al.  Quantum mechanical computations on very large molecular systems: The local self‐consistent field method , 1994, J. Comput. Chem..

[21]  Per Linse,et al.  Monte Carlo simulations of oppositely charged macroions in solution. , 2005, The Journal of chemical physics.

[22]  Adrian J Mulholland,et al.  Modelling enzyme reaction mechanisms, specificity and catalysis. , 2005, Drug discovery today.

[23]  Jiali Gao,et al.  Combined Quantum Mechanical and Molecular Mechanical Methods , 1999 .

[24]  R. Kierzek,et al.  The non-enzymatic hydrolysis of oligoribonucleotides VI. The role of biogenic polyamines. , 1999, Nucleic acids research.

[25]  J. Gao.  The hydration and solvent polarization effects of nucleotide bases. , 1994, Biophysical chemistry.

[26]  Alexander D. MacKerell,et al.  All‐atom empirical force field for nucleic acids: I. Parameter optimization based on small molecule and condensed phase macromolecular target data , 2000 .

[27]  A. Hinchliffe,et al.  Chemical Modelling: Applications and Theory , 2008 .

[28]  Manuel F. Ruiz-López,et al.  Calibration of the Quantum/Classical Hamiltonian in Semiempirical QM/MM AM1 and PM3 Methods , 2000 .

[29]  Jiali Gao,et al.  Methods and Applications of Combined Quantum Mechanical and Molecular Mechanical Potentials , 2007 .

[30]  Adrian J Mulholland,et al.  High-accuracy computation of reaction barriers in enzymes. , 2006, Angewandte Chemie.

[31]  Jing Kong,et al.  Lennard–Jones parameters for the combined QM/MM method using the B3LYP/6‐31G*/AMBER potential , 2005, J. Comput. Chem..

[32]  J. Harvey,et al.  Spin-forbidden CO ligand recombination in myoglobin. , 2004, Faraday discussions.

[33]  Keiji Morokuma,et al.  The IMOMO method: Integration of different levels of molecular orbital approximations for geometry optimization of large systems: Test for n‐butane conformation and SN2 reaction: RCl+Cl− , 1996 .

[34]  Christopher J. Woods,et al.  Biomolecular simulation and modelling: status, progress and prospects , 2008, Journal of The Royal Society Interface.

[35]  N. Pace,et al.  The RNA moiety of ribonuclease P is the catalytic subunit of the enzyme , 1983, Cell.

[36]  Donald G Truhlar,et al.  Generalized hybrid-orbital method for combining density functional theory with molecular mechanicals. , 2005, Chemphyschem : a European journal of chemical physics and physical chemistry.

[37]  Alexander D. MacKerell,et al.  All-atom empirical potential for molecular modeling and dynamics studies of proteins. , 1998, The journal of physical chemistry. B.

[38]  Donald G. Truhlar,et al.  Combining Self-Consistent-Charge Density-Functional Tight-Binding (SCC-DFTB) with Molecular Mechanics by the Generalized Hybrid Orbital (GHO) Method , 2004 .

[39]  William L. Jorgensen,et al.  Ab Initio Study Of Hydrogen-Bonded Complexes Of Small Organic Molecules With Water , 1998 .

[40]  W. Thiel,et al.  Hybrid Models for Combined Quantum Mechanical and Molecular Mechanical Approaches , 1996 .

[41]  P. Miller,et al.  Formation and repair of interstrand cross-links in DNA. , 2006, Chemical reviews.

[42]  M. Peräkylä,et al.  The base sequence dependent flexibility of linear single-stranded oligoribonucleotides correlates with the reactivity of the phosphodiester bond. , 2003, Organic & biomolecular chemistry.

[43]  Ronald R. Breaker,et al.  Kinetics of RNA Degradation by Specific Base Catalysis of Transesterification Involving the 2‘-Hydroxyl Group , 1999 .

[44]  Jiali Gao,et al.  Optimization of the Lennard‐Jones parameters for a combined ab initio quantum mechanical and molecular mechanical potential using the 3‐21G basis set , 1996 .

[45]  Richard A. Friesner,et al.  A mixed quantum mechanics/molecular mechanics (QM/MM) method for large‐scale modeling of chemistry in protein environments , 2000, J. Comput. Chem..

[46]  W. Stec,et al.  SURVEY AND SUMMARY Recent advances in the elucidation of the mechanisms of action of ribozymes , 2001 .

[47]  M. Karplus,et al.  Simulation of activation free energies in molecular systems , 1996 .

[48]  Lars Ridder,et al.  Quantum mechanical/molecular mechanical free energy simulations of the glutathione S-transferase (M1-1) reaction with phenanthrene 9,10-oxide. , 2002, Journal of the American Chemical Society.

[49]  J. Gao,et al.  A priori evaluation of aqueous polarization effects through Monte Carlo QM-MM simulations. , 1992, Science.

[50]  Christopher J. Woods,et al.  An efficient method for the calculation of quantum mechanics/molecular mechanics free energies. , 2008, The Journal of chemical physics.

[51]  Jiali Gao,et al.  Generalized hybrid orbital for the treatment of boundary atoms in combined quantum mechanical and molecular mechanical calculations using the semiempirical parameterized model 3 method , 2004 .

[52]  Adrian J Mulholland,et al.  Chemical accuracy in QM/MM calculations on enzyme-catalysed reactions , 2007, Chemistry Central journal.

[53]  Alexander D. MacKerell,et al.  All‐atom empirical force field for nucleic acids: II. Application to molecular dynamics simulations of DNA and RNA in solution , 2000 .

[54]  Adrian J Mulholland,et al.  Analysis of polarization in QM/MM modelling of biologically relevant hydrogen bonds , 2008, Journal of The Royal Society Interface.

[55]  M. Karplus,et al.  CHARMM: A program for macromolecular energy, minimization, and dynamics calculations , 1983 .

[56]  K. Merz,et al.  Combined Quantum Mechanical/Molecular Mechanical Methodologies Applied to Biomolecular Systems , 1999 .

[57]  Martin Karplus,et al.  Calculation of ground and excited state potential surfaces of conjugated molecules. I. Formulation and parametrization , 1972 .

[58]  M. Karplus,et al.  A combined quantum mechanical and molecular mechanical potential for molecular dynamics simulations , 1990 .

[59]  Donald G. Truhlar,et al.  Generalized Hybrid Orbital (GHO) Method for Combining Ab Initio Hartree-Fock Wave Functions with Molecular Mechanics , 2004 .

[60]  Iris Antes,et al.  Adjusted Connection Atoms for Combined Quantum Mechanical and Molecular Mechanical Methods , 1999 .

[61]  K. Taira,et al.  The Hydrolysis of RNA: From Theoretical Calculations to the Hammerhead Ribozyme-Mediated Cleavage of RNA. , 1998, Chemical reviews.

[62]  Alexander D. MacKerell,et al.  Progress toward chemical accuracy in the computer simulation of condensed phase reactions. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[63]  S. F. Boys,et al.  The calculation of small molecular interactions by the differences of separate total energies. Some procedures with reduced errors , 1970 .