Reparameterization of RNA χ Torsion Parameters for the AMBER Force Field and Comparison to NMR Spectra for Cytidine and Uridine

A reparameterization of the torsional parameters for the glycosidic dihedral angle, χ, for the AMBER99 force field in RNA nucleosides is used to provide a modified force field, AMBER99χ. Molecular dynamics simulations of cytidine, uridine, adenosine, and guanosine in aqueous solution using the AMBER99 and AMBER99χ force fields are compared with NMR results. For each nucleoside and force field, 10 individual molecular dynamics simulations of 30 ns each were run. For cytidine with AMBER99χ force field, each molecular dynamics simulation time was extended to 120 ns for convergence purposes. Nuclear magnetic resonance (NMR) spectroscopy, including one-dimensional (1D) 1H, steady-state 1D 1H nuclear Overhauser effect (NOE), and transient 1D 1H NOE, was used to determine the sugar puckering and preferred base orientation with respect to the ribose of cytidine and uridine. The AMBER99 force field overestimates the population of syn conformations of the base orientation and of C2′-endo sugar puckering of the pyrimidines, while the AMBER99χ force field’s predictions are more consistent with NMR results. Moreover, the AMBER99 force field prefers high anti conformations with glycosidic dihedral angles around 310° for the base orientation of purines. The AMBER99χ force field prefers anti conformations around 185°, which is more consistent with the quantum mechanical calculations and known 3D structures of folded ribonucleic acids (RNAs). Evidently, the AMBER99χ force field predicts the structural characteristics of ribonucleosides better than the AMBER99 force field and should improve structural and thermodynamic predictions of RNA structures.

[1]  C. Altona.  Conformational analysis of nucleic acids. Determination of backbone geometry of single‐helical RNA and DNA in aqueous solution , 2010 .

[2]  J. Šponer,et al.  Single Stranded Loops of Quadruplex DNA As Key Benchmark for Testing Nucleic Acids Force Fields. , 2009, Journal of chemical theory and computation.

[3]  D. Turner,et al.  Effects of Restrained Sampling Space and Nonplanar Amino Groups on Free-Energy Predictions for RNA with Imino and Sheared Tandem GA Base Pairs Flanked by GC, CG, iGiC or iCiG Base Pairs , 2009, Journal of chemical theory and computation.

[4]  Hirotaka Ode,et al.  Force field parameters for rotation around χ torsion axis in nucleic acids , 2008, J. Comput. Chem..

[5]  Darrin M York,et al.  Electrostatic interactions in the hairpin ribozyme account for the majority of the rate acceleration without chemical participation by nucleobases. , 2008, RNA.

[6]  D. York,et al.  Quantum mechanical/molecular mechanical simulation study of the mechanism of hairpin ribozyme catalysis. , 2008, Journal of the American Chemical Society.

[7]  Yu-Cheng Chang,et al.  Synthesis and solution conformation studies of 3-substituted uridine and pseudouridine derivatives. , 2008, Bioorganic & medicinal chemistry.

[8]  Helen M Berman,et al.  RNA backbone: consensus all-angle conformers and modular string nomenclature (an RNA Ontology Consortium contribution). , 2008, RNA.

[9]  C. Chow,et al.  Solution conformations of two naturally occurring RNA nucleosides: 3-methyluridine and 3-methylpseudouridine. , 2005, Bioorganic & medicinal chemistry.

[10]  D. Turner,et al.  RNA challenges for computational chemists. , 2005, Biochemistry.

[11]  Joanna Trylska,et al.  Exploring global motions and correlations in the ribosome. , 2005, Biophysical journal.

[12]  Modesto Orozco,et al.  Exploring the Essential Dynamics of B-DNA. , 2005, Journal of chemical theory and computation.

[13]  Thomas E Cheatham,et al.  Simulation and modeling of nucleic acid structure, dynamics and interactions. , 2004, Current opinion in structural biology.

[14]  Helen M Berman,et al.  RNA conformational classes. , 2004, Nucleic acids research.

[15]  Jeffery T. Davis.  G-quartets 40 years later: from 5'-GMP to molecular biology and supramolecular chemistry. , 2004, Angewandte Chemie.

[16]  F. J. Luque,et al.  Theoretical methods for the simulation of nucleic acids. , 2003, Chemical Society reviews.

[17]  Bojan Zagrovic,et al.  Solvent viscosity dependence of the folding rate of a small protein: Distributed computing study , 2003, J. Comput. Chem..

[18]  Pavel Hobza,et al.  Toward true DNA base-stacking energies: MP2, CCSD(T), and complete basis set calculations. , 2002, Journal of the American Chemical Society.

[19]  Sebastian Doniach,et al.  Rapid compaction during RNA folding , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[20]  Richard Lavery,et al.  Simulations of nucleic acids and their complexes. , 2002, Accounts of chemical research.

[21]  Eric J. Sorin,et al.  β-hairpin folding simulations in atomistic detail using an implicit solvent model1 , 2001 .

[22]  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..

[23]  Junmei Wang,et al.  How well does a restrained electrostatic potential (RESP) model perform in calculating conformational energies of organic and biological molecules? , 2000, J. Comput. Chem..

[24]  D. Beveridge,et al.  Nucleic acids: theory and computer simulation, Y2K. , 2000, Current opinion in structural biology.

[25]  P. Hobza,et al.  Global Minimum of the Adenine···Thymine Base Pair Corresponds Neither to Watson−Crick Nor to Hoogsteen Structures. Molecular Dynamic/Quenching/AMBER and ab Initio beyond Hartree−Fock Studies , 2000 .

[26]  T. Cheatham,et al.  Molecular dynamics simulation of nucleic acids: Successes, limitations, and promise * , 2000, Biopolymers.

[27]  Paul Tavan,et al.  A hybrid method for solutes in complex solvents: Density functional theory combined with empirical force fields , 1999 .

[28]  Andrew E. Torda,et al.  The GROMOS biomolecular simulation program package , 1999 .

[29]  P. Kollman,et al.  A modified version of the Cornell et al. force field with improved sugar pucker phases and helical repeat. , 1999, Journal of biomolecular structure & dynamics.

[30]  P. Kollman,et al.  Pathways to a protein folding intermediate observed in a 1-microsecond simulation in aqueous solution. , 1998, Science.

[31]  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 .

[32]  Claude Millot,et al.  A coupled density functional‐molecular mechanics Monte Carlo simulation method: The water molecule in liquid water , 1996 .

[33]  P. Kollman,et al.  A Second Generation Force Field for the Simulation of Proteins, Nucleic Acids, and Organic Molecules , 1995 .

[34]  A. J. Shaka,et al.  Excitation Sculpting in High-Resolution Nuclear Magnetic Resonance Spectroscopy: Application to Selective NOE Experiments , 1995 .

[35]  Kenneth M. Merz,et al.  Calculation of solvation free energies using a density functional/molecular dynamics coupled potential , 1993 .

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

[37]  P. Agris,et al.  Structure and conformation of the hypermodified purine nucleoside wyosine and its isomers: A comparison of coupling constants and distance geometry solutions , 1991 .

[38]  F. Seela,et al.  Syn-anti conformational analysis of regular and modified nucleosides by 1D 1H NOE difference spectroscopy: a simple graphical method based on conformationally rigid molecules , 1990 .

[39]  C. W. Hilbers,et al.  Nucleic acids and nuclear magnetic resonance. , 1988, European journal of biochemistry.

[40]  Martin J. Field,et al.  Free energy perturbation method for chemical reactions in the condensed phase: a dynamic approach based on a combined quantum and molecular mechanics potential , 1987 .

[41]  K. Wüthrich.  NMR of proteins and nucleic acids , 1988 .

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

[43]  H. Santos,et al.  Conformation of purine mononucleotides by H{H} and P{H} nuclear Overhauser effects , 1983 .

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

[45]  H. Santos,et al.  A proton relaxation study of the conformations of some purine mononucleotides in aqueous solution , 1982 .

[46]  P. A. Hart.  Conformation of mononucleotides and dinucleoside monophosphates. P[H] and H[H] nuclear Overhauser effects. , 1978, Biophysical journal.

[47]  P. Cary,et al.  The measurement of small nuclear overhauser effects in the 1H spectra of proteins, and their application to lysozyme , 1978 .

[48]  T. Pinnavaia,et al.  Alkali metal ion specificity in the solution ordering of a nucleotide, 5'-guanosine monophosphate , 1978 .

[49]  K. Wüthrich,et al.  NOE difference spectroscopy: A novel method for observing individual multiplets in proton NMR spectra of biological macromolecules , 1978 .

[50]  D. Davies.  CONFORMATIONS OF NUCLEOSIDES AND NUCLEOTIDES , 1978 .

[51]  G. Ciccotti,et al.  Numerical Integration of the Cartesian Equations of Motion of a System with Constraints: Molecular Dynamics of n-Alkanes , 1977 .

[52]  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.

[53]  R. E. Marsh,et al.  The crystal structure of uridine , 1975 .

[54]  F. Jordan,et al.  Ultrasonic relaxation evaluation of the thermodynamics of syn-anti glycosidic isomerization in adenosine. , 1974, Journal of the American Chemical Society.

[55]  P. Ts'o.  6 – BASES, NUCLEOSIDES, AND NUCLEOTIDES , 1974 .

[56]  M. Guéron,et al.  PROPERTIES OF PURINE NUCLEOTIDES STUDIED BY THE OVERHAUSER EFFECT: CONFORMATIONS, FLEXIBILITY, AGGREGATION , 1973, Annals of the New York Academy of Sciences.

[57]  K. Miura,et al.  Nucleosides and nucleotides. VI. Preparation of diribonucleoside monophosphates containing 4-thiouridine. , 1973, Journal of biochemistry.

[58]  M. Sundaralingam,et al.  Conformational analysis of the sugar ring in nucleosides and nucleotides. Improved method for the interpretation of proton magnetic resonance coupling constants. , 1973, Journal of the American Chemical Society.

[59]  M. Sundaralingam,et al.  Conformational analysis of the sugar ring in nucleosides and nucleotides. A new description using the concept of pseudorotation. , 1972, Journal of the American Chemical Society.

[60]  M. Guéron,et al.  Flexibility and conformations of guanosine monophosphates by the Overhauser effect. , 1972, Journal of the American Chemical Society.

[61]  R. E. Marsh,et al.  The Crystal Structure of Adenosine , 1972 .

[62]  P. Schimmel,et al.  Nanosecond relaxation processes in aqueous mononucleoside solutions. , 1971, Biochemistry.

[63]  M. Sundaralingam,et al.  Stereochemistry of nucleic acids and their constituents. XIX. Copper binding sites and mechanism of G-C selective denaturation of DNA. Crystal and molecular structures of guanine-copper(II) chloride and cytosine-copper(II) chloride complexes. , 1971, Journal of molecular biology.

[64]  M Sundaralingam,et al.  Stereochemistry of nucleic acids and their constituents. IX. The conformation of the antibiotic puromycin dihydrochloride pentahydrate. , 1969, Proceedings of the National Academy of Sciences of the United States of America.

[65]  D. Davies,et al.  Helix formation by guanylic acid. , 1962, Proceedings of the National Academy of Sciences of the United States of America.

[66]  J. Kraut,et al.  Crystal Structure of Adenosine-5′-phosphate , 1960, Nature.