James W. Caldwell

Development and testing of a general amber force field.

We describe here a general Amber force field (GAFF) for organic molecules. GAFF is designed to be compatible with existing Amber force fields for proteins and nucleic acids, and has parameters for most organic and pharmaceutical molecules that are composed of H, C, N, O, S, P, and halogens. It uses a simple functional form and a limited number of atom types, but incorporates both empirical and heuristic models to estimate force constants and partial atomic charges. The performance of GAFF in test cases is encouraging. In test I, 74 crystallographic structures were compared to GAFF minimized structures, with a root‐mean‐square displacement of 0.26 Å, which is comparable to that of the Tripos 5.2 force field (0.25 Å) and better than those of MMFF 94 and CHARMm (0.47 and 0.44 Å, respectively). In test II, gas phase minimizations were performed on 22 nucleic acid base pairs, and the minimized structures and intermolecular energies were compared to MP2/6‐31G* results. The RMS of displacements and relative energies were 0.25 Å and 1.2 kcal/mol, respectively. These data are comparable to results from Parm99/RESP (0.16 Å and 1.18 kcal/mol, respectively), which were parameterized to these base pairs. Test III looked at the relative energies of 71 conformational pairs that were used in development of the Parm99 force field. The RMS error in relative energies (compared to experiment) is about 0.5 kcal/mol. GAFF can be applied to wide range of molecules in an automatic fashion, making it suitable for rational drug design and database searching.

A Point-Charge Force Field for Molecular Mechanics Simulations of Proteins Based on Condensed-Phase Quantum Mechanical Calculations

Molecular mechanics models have been applied extensively to study the dynamics of proteins and nucleic acids. Here we report the development of a third‐generation point‐charge all‐atom force field for proteins. Following the earlier approach of Cornell et al., the charge set was obtained by fitting to the electrostatic potentials of dipeptides calculated using B3LYP/cc‐pVTZ//HF/6‐31G** quantum mechanical methods. The main‐chain torsion parameters were obtained by fitting to the energy profiles of Ace‐Ala‐Nme and Ace‐Gly‐Nme di‐peptides calculated using MP2/cc‐pVTZ//HF/6‐31G** quantum mechanical methods. All other parameters were taken from the existing AMBER data base. The major departure from previous force fields is that all quantum mechanical calculations were done in the condensed phase with continuum solvent models and an effective dielectric constant of ε = 4. We anticipate that this force field parameter set will address certain critical short comings of previous force fields in condensed‐phase simulations of proteins. Initial tests on peptides demonstrated a high‐degree of similarity between the calculated and the statistically measured Ramanchandran maps for both Ace‐Gly‐Nme and Ace‐Ala‐Nme di‐peptides. Some highlights of our results include (1) well‐preserved balance between the extended and helical region distributions, and (2) favorable type‐II poly‐proline helical region in agreement with recent experiments. Backward compatibility between the new and Cornell et al. charge sets, as judged by overall agreement between dipole moments, allows a smooth transition to the new force field in the area of ligand‐binding calculations. Test simulations on a large set of proteins are also discussed.

AMBER, a package of computer programs for applying molecular mechanics, normal mode analysis, molecular dynamics and free energy calculations to simulate the structural and energetic properties of molecules

We describe the development, current features, and some directions for future development of the AMBER package of computer programs. This package has evolved from a program that was constructed to do Assisted Model Building and Energy Refinement to a group of programs embodying a number of the powerful tools of modern computational chemistry-molecular dynamics and free energy calculations.

Protein structure prediction with a combined solvation free energy-molecular mechanics force field

Abstract Models of protein structure are frequently used to determine the physical characteristics of a protein when the crystal structure is not available. We developed a procedure to optimize such models, by use of a combined solvation free energy and molecular mechanics force field. Appropriately chosen atomic solvation parameters were defined using the criterion that the resulting protein model should deviate least from the crystal structure upon a forty picosecond molecular dynamics simulation carried out using the combined force field. Several tests were performed to refine the set of atomic solvation parameters which best complement the molecular mechanics forces. Four sets of parameters from the literature were tested and an empirically optimized set is proposed. The parameters are defined on a well characterized small molecule (alanyl dipeptide) and on the highly refined crystal structure of rat trypsin, and then tested on a second highly refined crystal structure of α-lytic protease. The new set...

Excited states and photochemistry of saturated molecules. VII. Potential energy surfaces in excited singlet states of methane

Potential energy surfaces are investigated for a number of low‐lying excited singlet states of methane, using a split valence plus Rydberg basis set and singly excited CI. Of the six minima found, the lowest two are valence states. The lowest minimum corresponds to the products 1 1B1 CH2+1 1Σg+ H2, in agreement with the observed threshold photochemistry, and is accessible by five separate routes from the lowest vertical state. The second valence minimum is a square planar structure. Of the four Rydberg minima detected, one is a local minimum on the otherwise dissociative B1 surface and two correspond closely to CH4+ structures previously determined. None of the minima have a structure from which the radical products CH3⋅+H⋅ are likely to be obtained.

Excited states and photochemistry of saturated molecules. Minimal plus Rydberg basis set calculations on the vertical spectra of CH4, C2H6, C3H8, and n-C4H10

Abstract Basis sets consisting of STO4G plus a set of one s and three p Rydberg functions are developed for methane, ethane, propane, and n -butane. These basis sets are then used to predict the vertical electronic spectra for the same four molecules using a limited CI. The results are found to be in reasonable agreement with experiment and with more sophisticated calculations on ethane and propane.

The effect of methylation of the 6 oxygen of guanine on the structure and stability of double helical DNA.

The effect of methylation of the O-6 position of guanine in short segments of double helical DNA has been investigated by molecular mechanical simulations on the sequences d(CGCGCG)2, d(CGC[OMG]CG)2, d(CGT[OMG]CG)2, d(CGC[OMC]CG/(CGCGCG), d(CGC[OMG]CG/d(CGTGCG), d(CGCGAATTCGCG)2 and d(CGCGAATTC[OMG]CG)2. Guanines methylated at the O-6 position are found to form hydrogen bonds of roughly equal strength to cytosine and thymine. The optimum structure of these modified base pairs are not dramatically different from normal GC pairs, but both involve some bifurcation of the proton donors of cytosine (4NH2) or thymine (3NH) between the guanine N3 and O6 groups.

An approach to polyatomic Franck-Condon integrals: Application to the photoelectron spectrum of water

Abstract An analytical method, based on harmonic oscillator expansions for each normal coordinate and the neglect of the Duschinsky A matrix, is presented for the prediction of Franck-Condon factors in polyatomic molecules from ab initio electronic wavefunctions. The method is tested against earlier theoretical results for H 2 and LiH and then applied to predict the vibrational structure for the first band of the photoelectron spectrum of water.

SCF Calculations on excited states

Abstract The formalism recently developed by Pople and co-workers for restricted Hartree—Fock calculations on high spin open shells is extended to a general treatment of singly excited states. The limitations of the method and possible alternative approaches are briefly discussed.

Excited states and photochemistry of saturated molecules. The vibrational structure in the electronic spectrum of ethane

Abstract Ab initio wavefunctions including single excitation CI are used to analyze the origin of the vibrational structure in the low-energy band of the electronic spectrum of ethane. The calculations suggest that the vibrational structure appears to be due to the overlapping progressions from two vertical states (1 E u and 1 A 2 u ), both of which are unstable to distortion to C 2 h symmetry, wherein they are characterized by significantly lengthened CC bonds.