Integrating sampling techniques and inverse virtual screening: toward the discovery of artificial peptide-based receptors for ligands.

A novel heuristic using an iterative select-and-purge strategy is proposed. It combines statistical techniques for sampling and classification by rigid molecular docking through an inverse virtual screening scheme. This approach aims to the de novo discovery of short peptides that may act as docking receptors for small target molecules when there are no data available about known association complexes between them. The algorithm performs an unbiased stochastic exploration of the sample space, acting as a binary classifier when analyzing the entire peptides population. It uses a novel and effective criterion for weighting the likelihood of a given peptide to form an association complex with a particular ligand molecule based on amino acid sequences. The exploratory analysis relies on chemical information of peptides composition, sequence patterns, and association free energies (docking scores) in order to converge to those peptides forming the association complexes with higher affinities. Statistical estimations support these results providing an association probability by improving predictions accuracy even in cases where only a fraction of all possible combinations are sampled. False positives/false negatives ratio was also improved with this method. A simple rigid-body docking approach together with the proper information about amino acid sequences was used. The methodology was applied in a retrospective docking study to all 8000 possible tripeptide combinations using the 20 natural amino acids, screened against a training set of 77 different ligands with diverse functional groups. Afterward, all tripeptides were screened against a test set of 82 ligands, also containing different functional groups. Results show that our integrated methodology is capable of finding a representative group of the top-scoring tripeptides. The associated probability of identifying the best receptor or a group of the top-ranked receptors is more than double and about 10 times higher, respectively, when compared to classical random sampling methods.

Interaction of brassinolide with essential amino acid residues: a theoretical approach.

The interaction of the most active natural brassinosteroid, brassinolide, with the twenty natural amino acids is studied applying the multiple minima hypersurface method to model the molecular interactions explicitly. The resulting thermodynamic data gives useful information about the amino acids with the greatest association for brassinolide and the stabilities of such complexes. Density functional theory (DFT) optimizations were further carried out to test the performance of semiempirical calculations. Additional calculations with a more accurate DFT method were performed to explore the formation of this type of molecular complexes. The semiempirical geometries and stability order of these complexes are in good agreement with the DFT calculations. Each group of amino acids possesses a preferential zone of interaction with brassinolide, forming the polar-charged amino acids the most stable complexes. This study could contribute to future investigations of the interaction of brassinosteroids with the receptor protein in plants.

Potential energy surfaces and Jahn-Teller effect on CH4...NO complexes.

The potential energy surface of the CH(4)...NO van der Waals complexes was explored at the RCCSD(T)/aug-cc-pVTZ level including the full counterpoise correction to the basis set superposition error. The Jahn-Teller distortion of the C(3v) configurations for the CH bonded and CH(3) face complexes was analyzed. From this distortion, two A(') and A(") adiabatic surfaces were considered. The estimated zero point energy of C(s) configurations is above the barrier of the C(3v) ones. Therefore, the CH(3) face complexes are dynamic Jahn-Teller systems. The D(0) (140 cm(-1) for A(") state and 100 cm(-1) for A(')) values obtained are in good agreement with the experimental values (103+/-2 cm(-1)) recently reported.

Subphthalocyanine-fused dimers and trimers: synthetic, electrochemical, and theoretical studies.

Subphthalocyanine (SubPc)-fused dimers and trimers bearing fluorine, iodine, and thioether peripheral substituents were synthesized and characterized. Absorption spectroscopy and electrochemical studies revealed (i) that the substituents have a strong effect on the electronic properties of the macrocycles and (ii) that there is good communication between the subphthalocyaninic moieties within the oligomeric structures. Theoretical calculations at DFT/6-31G(d,p) computational level and electron density studies support the experimental findings. The frontier orbitals in the dimers and trimers were also shown to be significantly altered with respect to those of SubPcs as a consequence of the extension of the conjugation associated with symmetry breaking. Time-dependent density functional theory calculations reproduced the differences observed in the UV-vis spectra of the fused dimers and the monomeric SubPcs.