ABSTRACT
The synthesis, in vitro evaluation and conformational study of penetratin and structurally related derivatives acting as antibacterial agents are reported. Among the compounds evaluated here, two methionine sulphoxide derivatives (RQIKIWFQNRRM[O]KWKK-NH2 and RQIKIFFQNRRM[O]KFKK-NH2 ) exhibited the strongest antibacterial effect in this series. In order to better understand the antimicrobial activity obtained for these peptides, we performed an exhaustive conformational analysis using different approaches. Molecular dynamics simulations were performed using two different media (water and trifluoroethanol/water). The results of these theoretical calculations were corroborated using experimental CD measurements. The electronic study for these peptides was carried out using molecular electrostatic potentials obtained from RHF/6-31G(d) calculations. In addition, the non-apeptide RQIRRWWQR-NH2 showed strong inhibitory action against the Gram-negative and Gram-positive bacteria tested in this study.
Subject(s)
Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Carrier Proteins/chemistry , Carrier Proteins/pharmacology , Amino Acid Sequence , Bacterial Infections/drug therapy , Cell-Penetrating Peptides , Humans , Models, Molecular , Molecular Sequence Data , Protein ConformationABSTRACT
Using a conformational systematic search combined with semiempirical and ab initio (RHF/3-21G and RHF/6-31G(d)) calculations, the conformational space of bullacin B was examined for the first time. In addition, molecular dynamics simulations were carried out to better evaluate the conformational behavior of this acetogenin. Our results indicate that bullacin B possesses a significant molecular flexibility. Although many different conformations were identified, at ab initio level, the L forms were energetically mostly preferred. Our results support the use of molecular dynamics simulations for this compound suggesting that a combined decane/water system is a good solvent system to simulate the biological environment of this molecule acting as inhibitor of complex I.
Subject(s)
Electron Transport Complex I/antagonists & inhibitors , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Furans/chemistry , Furans/pharmacology , Lactones/chemistry , Lactones/pharmacology , Models, Molecular , Molecular Conformation , Quantum Theory , Static Electricity , Surface PropertiesABSTRACT
The multidimensional Potential Energy Hypersurface (PEHS) for the cyclononane molecule was comprehensively investigated at the Hartree-Fock (HF), and Density Functional Theory (DFT) levels of theory. Second-order Møller-Plesset perturbation theory (MP2) optimizations were also carried out to confirm the low-energy conformations. The previously reported Geometrical Algorithm to Search Conformational Space (GASCOS) has been used to generate the starting geometries for the conformational analysis. The GASCOS algorithm combined with ab initio and DFT optimization permits searching of the potential energy hypersurface for all minimum-energy conformations as well as transition structures connecting the low-energy forms. The search located all previously reported structures together with 11 transition states, some of which were not found by earlier searching techniques. Altogether, 16 geometries (five low-energy conformations and 11 transition states) were found to be important for a description of the conformational features of cyclononane. RB3LYP/aug-cc-pVTZ//RB3LYP/6-31G(d) calculations suggest a conformational mixture between the twist boat-chair and twist chair-boat conformations as the preferred forms. In addition only the twist chair-chair conformation with 1.52 kcal/mol above the global minimum should contribute somewhat to the equilibrium mixture of conformations. Our results allow us to form a concise idea about the internal intricacies of the 9D vector space describing the conformation of cyclononane as well as the associated conformational potential energy hypersurface of nine independent variables.
