Valence Force Fields as a Tool in Vibrational Spectroscopy and Molecular Mechanics

Force field calculations on conjugated molecules are discussed. The discussion is based on the experience of a series of overlay calculations, recently carried out, where the transferability of force constants was thoroughly studied. Successful applications as well as limitations of the constructed force field are described. The effects of nonbonded interactions are recognized as the most serious restriction of the transferability of valence force fields, and it is suggested that the molecular mechanics method, where the nonbonded interactions are taken explicitly into account, would be advantageous. The treatment of potential energy in the molecular mechanics method is briefly described and theconnections between valence force constants and potential energy parameters in this method are discussed

Optimization of parameters of nonbonded interactions in a spectroscopically determined force field

A procedure is given by which parameters of nonbonded interactions in a molecular mechanics energy function can be optimized for maximum compatibility with ab initio force fields and structures. The method is based on a previously derived transformation of ab initio valence parameters to the molecular mechanics formalism. Explicit analytical expressions for the derivatives of the molecular mechanics force constants and reference geometry parameters with respect to the parameters of the nonbonded interactions are derived. The form of the goodness-of-fit function is discussed. A first application to a set of alanine dipeptides is described.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/30924/1/0000594.pd

Conversion of ab-initio force fields and structures to molecular mechanics energy functions

The rapid development of computers in recent years has brought increasingly complex compounds into the range of high level ab-initio calculations. Such calculations produce valuable results which in many cases would be difficult or even impossible to obtain, with comparable accuracy, in any other way (Fogarasi & Pulay, Annu. Rev. Phys. Chem. 35, 191, 1984). Thus, it is highly desirable to be able to utilize these results in the construction of potential energy functions used in molecular mechanics (MM), molecular dynamics and Monte-Carlo calculations. For instance, the significance of quadratic cross terms in MM energy functions is still insufficiently explored (Lii & Allinger, J. Am. Chem. Soc. 111, 8566, 1989). In order to make possible the complete utilization of ab-initio results in MM calculations, we have developed a method by which scaled ab-initio (or empirical) force fields and structures can be directly converted to MM potential energy parameters, without sacrificing any of the original accuracy with regard to vibrational frequencies or structure. Here we briefly outline the conversion procedure, a more complete analysis being published separately.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/29587/1/0000676.pd

Utilization of overlay and AB initio force fields in the construction of empirical potential energy functions for conjugated molecules

The optimization of the parameters in the molecular mechanics method is discussed. The utilization of spectroscopic force fields is described, and the advantages of utilizing molecular symmetry in the optimization of the parameters on the vibrational frequencies are stressed. The development of the potential functions for the benzene ring and for the vinyl group is briefly described, and the the application of these functions to calculate the geometry of the styrene molecule is discussed.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/28713/1/0000534.pd

Peptide Conformer Acidity Analysis of Protein Flexibility Monitored by Hydrogen Exchange†

ABSTRACT: The amide hydrogens that are exposed to solvent in the high-resolution X-ray structures of ubiquitin, FK506-binding protein, chymotrypsin inhibitor 2, and rubredoxin span a billion-fold range in hydroxide-catalyzed exchange rates which are predictable by continuum dielectric methods. To facilitate analysis of transiently accessible amides, the hydroxide-catalyzed rate constants for every backbone amide of ubiquitin were determined under near physiological conditions. With the previously reported NMR-restrained molecular dynamics ensembles of ubiquitin (PDB codes 2NR2 and 2K39) used as representations of the Boltzmann-weighted conformational distribution, nearly all of the exchange rates for the highly exposed amides were more accurately predicted than by use of the high-resolution X-ray structure. More strikingly, predictions for the amide hydrogens of the NMR relaxation-restrained ensemble that become exposed to solvent in more than one but less than half of the 144 protein conformations in this ensemble were almost as accurate. In marked contrast, the exchange rates for many of the analogous amides in the residual dipolar coupling-restrained ubiquitin ensemble are substantially overestimated, as was particularly evident for the Ile 44 to Lys 48 segment which constitutes the primary interaction site for the proteasome targeting enzymes involved in polyubiquitylation. For both ensembles, “excited state ” conformers in this active site region having markedly elevated peptide acidities are represented at a population level that is 102 to 103 abov

Parameterization of Peptide 13 C Carbonyl Chemical Shielding Anisotropy in Molecular Dynamics Simulations Effects of Dynamic Local Distortions on 13 C Carbonyl NMR Relaxation.

NMR chemical shielding anisotropy (CSA) relaxation is an important tool in the study of dynamical processes in proteins and nucleic acids in solution. Herein, we investigate how dynamical variations in local geometry affect the chemical shielding anisotropy relaxation of the carbonyl carbon nucleus, using the following protocol: 1) Using density functional theory, the carbonyl 13 C′ CSA is computed for 103 conformations of the model peptide group N -methylacetamide (NMA). 2) The variations in computed 13 C′ CSA parameters are fitted against quadratic hypersurfaces containing cross terms between the variables. 3) The predictive quality of the CSA hypersurfaces is validated by comparing the predicted and de novo calculated 13 C′ CSAs for 20 molecular dynamics snapshots. 4) The CSA fluctuations and their autocorrelation and cross correlation functions due to bond-length and bond-angle distortions are predicted for a chemistry Harvard molecular mechanics (CHARMM) molecular dynamics trajectory of Ca 2+ -saturated calmodulin and GB3 from the hypersurfaces, as well as for a molecular dynamics (MD) simulation of an NMA trimer using a quantum mechanically correct forcefield. We find that the fluctuations can be represented by a 0.93 scaling factor of the CSA tensor for both R 1 and R 2 relaxations for residues in helix, coil, and sheet alike. This result is important, as it establishes that 13 C′ relaxation is a valid tool for measurement of interesting dynamical events in proteins.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/56090/1/1375_ftp.pd