Showing papers by "Alexander Tropsha published in 1995"

Cross-validated R2-guided region selection for comparative molecular field analysis: a simple method to achieve consistent results.

Abstract: Comparative Molecular Field Analysis (CoMFA) is one of the most powerful modern tools for quantitative structure-activity relationship studies. The CoMFA predictability is conventionally characterized by a cross-validated correlation coefficient R2 (q2). Our CoMFA investigation of 4 datasets, including 7 cephalotaxine esters, 20 5-HT1A receptor ligands, 59 inhibitors of HIV protease, and 21 steroids reveals that the q2 value is sensitive to the overall orientation of superimposed molecules on a computer terminal and can vary by as much as 0.5q2 units when the orientation is varied by systematic rotation. To optimize CoMFA, we have developed a new routine, cross-validated R2-guided region selection (q2-GRS). We first subdivide the rectangular lattice obtained initially with conventional CoMFA into 125 small boxes and perform 125 independent analyses using probe atoms placed within each box with the step size of 1.0 A. We then select only those small boxes for which a q2 is higher than a specified optimal cutoff value. Finally, we repeat CoMFA with the union of small boxes selected at the previous step. Four datasets described above were used to validate this new q2-GRS routine. In each case we have obtained an orientation-independent, high q2, exceeding the one obtained with the conventional CoMFA. This method shall be used routinely in the future CoMFA studies to guarantee the reproducibility of the reported q2 values.

Relative Binding Free Energies of Peptide Inhibitors of HIV-1 Protease: The Influence of the Active Site Protonation State

Abstract: Hydrogen bonding plays an important role in the stabilization of complexes between HIV-1 protease (HIV-1 PR) and its inhibitors. The adequate treatment of the protease active site protonation state is important for accurate molecular simulations of the protonation state is important for accurate molecular simulations of the protease-inhibitor complexes. We have applied the free energy simulation/thermodynamic cycle approach to evaluate the relative binding affinities of the S vs R isomers of the U85548E inhibitor of the protease. Several mono- and diprotonation states of the catalytic aspartic acid residues of the protease active site were considered in the course of molecular simulations. The calculated difference in binding free energy of the S vs R isomers strongly depended on the location of proton(s), but in all cases the binding free energy of the S inhibitor was higher. On the basis of our calculations, we propose that in the HIV-1 PR-inhibitor complex only one catalytic aspartic acid residue is protonated and that the binding free energy of the S isomer is ca. 2.8 kcal/mol higher than that of the R isomer. The accuracy of these predictions shall be evaluated when binding affinities of both isomers become available.

Thermodynamic parameters for the helix-coil transition of oligopeptides: molecular dynamics simulation with the peptide growth method

Abstract: The helix-coil transition equilibrium of polypeptides in aqueous solution was studied by molecular dynamics simulation. The peptide growth simulation method was introduced to generate dynamic models of polypeptide chains in a statistical (random) coil or an alpha-helical conformation. The key element of this method is to build up a polypeptide chain during the course of a molecular transformation simulation, successively adding whole amino acid residues to the chain in a predefined conformation state (e.g., alpha-helical or statistical coil). Thus, oligopeptides of the same length and composition, but having different conformations, can be incrementally grown from a common precursor, and their relative conformational free energies can be calculated as the difference between the free energies for growing the individual peptides. This affords a straightforward calculation of the Zimm-Bragg sigma and s parameters for helix initiation and helix growth. The calculated sigma and s parameters for the polyalanine alpha-helix are in reasonable agreement with the experimental measurements. The peptide growth simulation method is an effective way to study quantitatively the thermodynamics of local protein folding.

Pseudotorsional OCCO backbone angle as a single descriptor of protein secondary structure

Abstract: Protein secondary structure is conventionally identified using characteristic ranges of two backbone torsional angles phi and psi. We suggest that the secondary structure can be adequately characterized by a single descriptor, the Oi-1Ci-1CiOi (where i is the residue number) pseudotorsional backbone angle. A set of 102 structurally distinct protein chains from the Protein Data Bank was used to evaluate the adequacy of this descriptor. We find that a specific range of OCCO angles corresponds to each major secondary structure. The complete range of OCCO angles (-180 degrees to 179 degrees) was broken into 18 consecutive subranges of 20 degrees each, and each subrange was assigned a letter. Thus, the OCCO profiles for each protein in the database were "translated" into a sequence of letters. The Needleman-Wunsch primary sequence alignment algorithm was then used for secondary/tertiary structure comparison and alignment. Preliminary results indicate that this new approach has a significant potential for rapid identification of fold families in the Protein Data Bank.

Rapid protein structure classification using one-dimensional structure profiles on the BioSCAN parallel computer

Abstract: Rapid growth of protein structures database in recent years requires an effective approach for objective comparison and classification of deposited protein structures. We describe a novel method for structure comparison and classification based on the alignment of one-dimensional structure profiles. These profiles are obtained by calculating the OCCO pseudodihedral angles (formed by O-C-C-O atoms of carbonyl groups of consecutive amino acid residues) from protein three-dimensional coordinates. These angle measurements are then converted into a 24 letter alphabet, and the protein structures are represented by sequences of letter from this alphabet. The BioSCAN parallel computer, designed for primary sequence alignment, is used to rapidly align and classify these one-dimensional structure profiles. We have developed and implemented weighted scoring matrix to identify structural classes based on commonly found structural motifs. The results of our experiments are in good agreement with the traditional protein structure classification schemes. One-dimensional structure profiles significantly improve efficiency of structure comparison and classification.

Semi-empirical calculations of intramolecular acyl transfer in cis-enols of o-aroyl acetylacetones

Abstract: Intramolecular acyl transfer was studied in eight aroyl derivatives of cis enols of acetylacetone using various semiempirical hamiltonians. The transition state geometry and activation energy for each derivative is reported. A reaction rate relative to that for the O-benzoyl derivative was calculated for each member in the series. The calculated relative rate constants were correlated to the substituent electronic constants, σ, and to experimental relative rate constants. Good correlations were obtained in both cases with the exceptions of the p-chloro and m-nitro aroyl groups. The rates of acyl transfer were enhanced by electron withdrawing aroyl groups. Calculations with the PM3 hamiltonians reproduced experimental trends better than using AM1.