F.D. Suvire

Characteristics of Ramachandran maps of L-alanine diamides as computed by various molecular mechanics, semiempirical and ab initio MO methods. A search for primary standard of peptide conformational stability

Abstract The optimized geometries and relative energies obtained by four force field and two semi-empirical methods were compared with ab initio results computed for formyl- L -alaninamide. Not all methods yielded the same number of minimum energy conformers. Furthermore, while the optimized geometries of the conformers found were comparable, the computed relative energies varied substantially. Also, the force field calculations produced Ramachandran maps that did not even have the appearance of the ab initio Ramachandran map. Correlating the ab initio relative energies (Δ E ) or free energy (Δ G ) with the log of relative populations, ln( p x / p γ L ), led to linear relationships from which four conformers deviated; two of them (α L and e L ) were overly destabilized and two of them (γ L and γ D ) were over-stabilized. It is suggested that, after such deviations are corrected, a primary standard may be obtained that might be useful in further investigations related to force-field parametrization as well as protein folding.

A GEOMETRICAL ALGORITHM TO SEARCH THE CONFORMATIONAL SPACE (GASCOS) OF FLEXIBLE MOLECULES

We report a geometrical algorithm to search the conformational space (GASCOS), with the goal to evaluate, in a computationally effective way, all possible conformations of a flexible molecule. The present report itself consists of two parts. The first part is primarily devoted to the mathematical principles on which our approach is based. The basic principles are illustrated in terms of the conformational aspect of small normal hydrocarbons: CnH2n12. In the second half of the paper we apply the geometrical approach to a set of specific chemical problems namely, partially fluorinated propanes are used in order to determine the steric requirement and, therefore, the spatial proximity of the terminal atoms during multiple internal rotations. In one type of application the torsion about the bond was regarded as a continuous variable by choosing the increment in torsional angle (Du )t o be small, such as 58. In this approach we were able to assess the spatial requirement and therefore any possible collision of rotating moieties. In an other type of application Du was assumed to be as large as 1208, thus the internal rotational angle was regarded as a variable that can assume only discrete values (g 1 , a, g 2 ). In this fashion, the program could generate an input file for empirical force field, semi-empirical MO or ab initio molecular computations within the framework of multidimensional conformational analysis (MDCA). In other words GASCOS could become the driver program for any energy calculating software. Finally, when an unusually short distance was obtained by the GASCOS method, it was then possible to consider such an occurrence as an indicator of a probable conformational catastrophe. q 1999 Elsevier Science B.V. All rights reserved.

An ab initio exploratory study of side chain conformations for selected backbone conformations of N-acetyl-l-glutamine-N-methylamide

Abstract The backbone potential energy surface (PES) (Ramachandran map) of N-acetyl- l -glutamine-N-methylamide has been studied at a,a side-chain orientation. Side-chain PESs at selected backbone conformations (γ l and β l ) were also studied. Side-chain–backbone interactions were analyzed in terms of energy and geometry.

Binding mechanism of RGD and its mimetics to receptor GPIIb/IIIa. A theoretical study

Abstract In order to better understand, at a sub-molecular level, the minimal structural requirements for the recognition process in the platelet aggregation inhibitory activity, a series of RGD mimetics were examined as fibrinogen receptor antagonists variants. We simulate the electronic interactions between RGD with its biological receptor in terms of smaller molecules. MeCOO− was used to mimic the side chain of deprotonated Asp and Meguanidinium group mimicked the side chain of the protonated Arg. Alternative moieties present on the RGD mimetics were also studied in this report. AM1; RHF/3-21G; B3LYP/6-31++G∗∗ in the gas phase. Also, B3LYP/6-31++G∗∗ calculations using the IPCM solvation model were carried out for all the complexes. Our results indicate that high level of theory calculations and the inclusion of solvent effects are crucial in order to obtain satisfactory of accuracy in the electronic distributions of these compounds.

Exploratory molecular orbital calculations on the keto and enol forms of selected antifungals and those of side-chain substituted acetophenone model compounds

Abstract Conformational potential energy surfaces were generated using the semiempirical AM1 method for selected α -substituted arylpropanoids. The global minima were subjected to full AM1 geometry optimizations. Keto–enol tautomerization energies were also computed at the AM1 level. The results obtained were compared to those of Simple Huckel Molecular Orbital calculations. Antifungal activities of the compounds studied were reported as minimal inhibitory concentration values. These values were correlated with computed molecular parameters. A set of α -substituted acetophenones (using Me, F and Cl as substituents) were also studied, as model compounds for the antifungals, at the AM1 and the RHF/STO-3G levels of theory. The enolization energies were calculated at both levels of theory.

Partially relaxed ring closure conditions for geometrical algorithm to search the conformational space for minimum energy conformations

Abstract We have reported a systematic search method, GASCOS, for open chain compounds. An extension to cyclic structures was recently reported. In this paper, we propose a more complete range of tolerance for some of the bond angles of the cyclic molecules studied. Specifically, we will accept that three consecutive bond angles associated with the ring closure condition can vary their values between certain previously fixed limits. We also introduce the concept of “family” which permit the “agglutination” of neighborhood configurations when their number is too large. Two small systems, cyclopentane and cyclohexane, were chosen to illustrate the GASCOS partially relaxed ring closure method in optimizing cyclic structures.

An analytic ring closure condition for geometrical algorithm to search the conformational space

Abstract The recently reported geometrical algorithm to search the conformational space (GASCOS) scans conformational space exhaustively using an internal coordinate tree search. Using only geometrical operations and a set of criteria for eliminating chemically unreasonable atomic arrangements, the algorithm generates starting geometries for optimizations by molecular mechanics or by molecular orbital procedures. Up until now GASCOS has been used for linear structures, but an extension to cyclic structures is reported here.

An exploratory study of side-chain-backbone interaction in selected conformations of N-acetyl-L-glutamate-N-methylamide. An ab initio study

Abstract The Ramachandran map of N -acetyl- l -glutamate- N -methylamide has been explored using a, a side-chain (SC) conformation. Also, with fixed backbone (BB) conformations (γ l and β l ) the SC conformational potential energy surfaces were studied. The relative stabilities of the various conformers were analysed in terms of SC–BB interactions. The dynamic chirality of the glutamate SC was investigated and compared to that of the butyrate ion.

A matrix representation for the geometrical algorithm to search the conformational space (GASCOS) for flexible linear molecules

Abstract Matrix representation has been developed for two successive rotations ( α , β ) in order to calculate easily the atomic coordinates (as well as non-bonded distances) from the initial molecular geometry and the dihedral angles applied ( α , β ). It has been shown that the numerical quantities in the matrices involved, can be calculated from the initial molecular configuration. In addition to these matrices only analytic functions were needed with explicit dependence on the dihedral angles ( α , β ) to calculate the position vectors of the constituting atoms. Hopefully, the generalized method can be adapted to peptide folding with particular emphasis to the side-chain/side chain interaction.

Theoretical study of the conformational energy hypersurface of cyclotrisarcosyl

The multidimensional Conformational Potential Energy Hypersurface (PEHS) of cyclotrisarcosyl was comprehensively investigated at the DFT (B3LYP/6-31G(d), B3LYP/6-31G(d,p) and B3LYP/6-311++G(d,p)), levels of theory. The equilibrium structures, their relative stability, and the Transition State (TS) structures involved in the conformational interconversion pathways were analyzed. Aug-cc-pVTZ//B3LYP/6-311++G(d,p) and MP2/6-31G(d)//B3LYP/6-311++G(d,p) single point calculations predict a symmetric cis-cis-cis crown conformation as the energetically preferred form for this compound, which is in agreement with the experimental data. The conformational interconversion between the global minimum and the twist form requires 20.88 kcal mol-1 at the MP2/6-31G(d)//B3LYP/6-311++G(d,p) level of theory. Our results allow us to form a concise idea about the internal intricacies of the PEHSs of this cyclic tripeptide, describing the conformations as well as the conformational interconversion processes in this hypersurface. In addition, a comparative analysis between the conformational behaviors of cyclotrisarcosyl with that previously reported for cyclotriglycine was carried out