AMBER Parm99 Research Articles

Calibration of force-field dependency in free energy landscapes of peptide conformations by quantum chemical calculations.

The free energy landscapes of peptide conformations were calibrated by ab initio quantum chemical calculations, after the enhanced conformational diversity search using the multicanonical molecular dynamics simulations. Three different potentials of mean force for an isolated dipeptide were individually obtained by the multicanonical molecular dynamics simulations using the conventional force fields, AMBER parm94, AMBER parm96, and CHARMm22. Each potential of mean force was then calibrated based upon the umbrella sampling algorithm from the adiabatic energy map that was calculated separately by the ab initio molecular orbital method, and all of the calibrated potentials of mean force coincided well. The calibration method was also applied to the simulations of a peptide dimer in explicit water models, and it was shown that the calibrated free energy landscapes did not depend on the force field used in the classical simulations, as far as the conformational space was sampled well. The current calibration method fuses the classical free energy calculation with the quantum chemical calculation, and it should generally make simulations for biomolecular systems much more reliable when combining with enhanced conformational sampling.

Peptide free energy landscapes calibrated by molecular orbital calculations.

Free energy landscapes of peptide conformations werecalibrated by ab initiomolecular orbital calculations, after enhancedconformational sampling using the multicanonical molecular dynamicssimulations. Three different potentials of mean force for an isolateddipeptide were individually obtained using the conventional force fields,AMBER parm94, AMBER parm96, and CHARMm22. Each potential ofmean force was calibrated based on the umbrella sampling algorithm fromthe adiabatic energy map that was calculated separately by the abinitiomolecular orbital method. All the calibrated potentials of mean forcecoincided well. The calibration was applied to a peptide in explicit water,and the calibrated free energy landscapes did not depend on the force fieldused in conformational sampling, as far as the conformational space waswell sampled.

Energy landscape of a peptide consisting of alpha-helix, 3(10)-helix, beta-turn, beta-hairpin, and other disordered conformations.

The energy landscape of a peptide [Ace-Lys-Gln-Cys-Arg-Glu-Arg-Ala-Nme] in explicit water was studied with a multicanonical molecular dynamics simulation, and the AMBER parm96 force field was used for the energy calculation. The peptide was taken from the recognition helix of the DNA-binding protein, c-MYB: A rugged energy landscape was obtained, in which the random-coil conformations were dominant at room temperature. The CD spectra of the synthesized peptide revealed that it is in the random state at room temperature. However, the 300 K canonical ensemble, Q(300K), contained alpha-helix, 3(10)-helix, beta-turn, and beta-hairpin structures with small but notable probabilities of existence. The complete alpha-helix, imperfect alpha-helix, and random-coil conformations were separated from one another in the conformational space. This means that the peptide must overcome energy barriers to form the alpha-helix. The overcoming process may correspond to the hydrogen-bond rearrangements from peptide-water to peptide-peptide interactions. The beta-turn, imperfect 3(10)-helix, and beta-hairpin structures, among which there are no energy barriers at 300 K, were embedded in the ensemble of the random-coil conformations. Two types of beta-hairpin with different beta-turn regions were observed in Q(300K). The two beta-hairpin structures may have different mechanisms for the beta-hairpin formation. The current study proposes a scheme that the random state of this peptide consists of both ordered and disordered conformations. In contrast, the energy landscape obtained from the parm94 force field was funnel like, in which the peptide formed the helical conformation at room temperature and random coil at high temperature.

Free-energy analysis of enzyme-inhibitor binding: aspartic proteinase-pepstatin complexes.

Expeditious in silico determinations of the free energies of binding of a series of inhibitors to an enzyme are of immense practical value in structure-based drug design efforts. Some recent advances in the field of computational chemistry have rendered a rigorous thermodynamic treatment of biologic molecules feasible, starting from a molecular description of the biomolecule, solvent, and salt. Pursuing the goal of developing and making available a software for assessing binding affinities, we present here a computationally rapid, albeit elaborate, methodology to estimate and analyze the molecular thermodynamics of enzyme-inhibitor binding with crystal structures as the point of departure. The complexes of aspartic proteinases with seven inhibitors have been adopted for this study. The standard free energy of complexation is considered in terms of a thermodynamic cycle of six distinct steps decomposed into a total of 18 well-defined components. The model we employed involves explicit all-atom accounts of the energetics of electrostatic interactions, solvent screening effects, van der Waals components, and cavitation effects of solvation combined with a Debye-Huckel treatment of salt effects. The magnitudes and signs of the various components are estimated using the AMBER parm94 force field, generalized Born theory, and solvent accessibility measures. Estimates of translational and rotational entropy losses on complexation as well as corresponding changes in the vibrational and configurational entropy are also included. The calculated standard free energies of binding at this stage are within an order of magnitude of the observed inhibition constants and necessitate further improvements in the computational protocols to enable quantitative predictions. Some areas such as inclusion of structural adaptation effects, incorporation of site-dependent amino acid pKa shifts, consideration of the dynamics of the active site for fine-tuning the methodology are easily envisioned. The present series of studies, nonetheless, creates potentially useful qualitative information for design purposes on what factors favor protein-drug binding. The net binding free energies are a result of several competing contributions with 6 of the 18 terms favoring complexation. The nonelectrostatic contributions (i.e., the net van der Waals interactions) and the differential cavitation effects favor binding. Electrostatic contributions show considerable diversity and turn out to be favorable in a consensus view for the seven aspartic proteinase-inhibitor complexes examined here. Implications of these observations to drug design are discussed.

Free Energy Analysis of Protein–DNA Binding: The EcoRI Endonuclease–DNA Complex

A detailed theoretical analysis of the thermodynamics and functional energetics of protein–DNA binding in the EcoRI endonuclease–DNA complex is presented. The standard free energy of complexation is considered in terms of a thermodynamic cycle of seven distinct steps decomposed into a total of 24 well-defined components. The model we employ involves explicit all-atom accounts of the energetics of structural adaptation of the protein and the DNA upon complex formation; the van der Waals and electrostatic interactions between the protein and the DNA; and the electrostatic polarization and screening effects, van der Waals components, and cavitation effects of solvation. The ion atmosphere of the DNA is described in terms of a counterion condensation model combined with a Debye–Huckel treatment of added salt effects. Estimates of entropy loss due to decreased translational and rotational degrees of freedom in the complex relative to the unbound species based on classical statistical mechanics are included, as well as corresponding changes in the vibrational and configurational entropy. The magnitudes and signs of the various components are estimated from the AMBER parm94 force field, generalized Born theory, solvent accessibility measures, and empirical estimates of quantities related to ion release.The calculated standard free energy of formation, −11.5 kcal/mol, agrees with experiment to within 5 kcal/mol. This net binding free energy is discerned to be the resultant of a balance of several competing contributions associated with chemical forces as conventionally defined, with 10 out of 24 terms favoring complexation. Contributions to binding compounded from subsets of the 24 components provide a basis for advancing a molecular perspective of binding in terms of structural adaptation, electrostatics, van der Waals interactions, hydrophobic effects, and small ion reorganization and release upon complexation. The van der Waals interactions and water release favor complexation, while electrostatic interactions, considering both intramolecular and solvation effects, prove unfavorable. Analysis of individual contributions to the standard free energy of complexation at the nucleotide and amino acid residue level highlights the role of contact interactions as well as context effects. Some patterns in compensation effects among the various terms are identified and discussed.