Biomedical subjects

Sergio Madurga

Publications and source records attributed to Sergio Madurga.

4 recordsLinked to original sources

PubMed2006

Evolutionary computation and multimodal search: a good combination to tackle molecular diversity in the field of peptide design.

The awesome degree of structural diversity accessible in peptide design has created a demand for computational resources that can evaluate a multitude of candidate structures. In our specific case, we translate the peptide design problem to an optimization problem, and use evolutionary computation (EC) in tandem with docking to carry out a combinatorial search. However, the use of EC in huge search spaces with different optima may pose certain drawbacks. For example, EC is prone to focus a search in the first good region found. This is a problem not only because of the undesirable and automatic rejection of potentially good search space regions, but also because the found solution may be extremely difficult to synthesize chemically or may even be a false docking positive. In order to avoid rejecting potentially good solutions and to maximize the molecular diversity of the search, we have implemented evolutionary multimodal search techniques, as well as the molecular diversity metric needed by the multimodal algorithms to measure differences between various regions of the search space.

Algorithms↗

PubMed2006

Conformational analysis of a potent SSTR3-selective somatostatin analogue by NMR in water solution.

The three-dimensional structure of a potent SSTR3-selective analogue of somatostatin, cyclo(3-14)H-Cys(3)-Phe(6)-Tyr(7)-D-Agl(8)(N(beta) Me, 2-naphthoyl)-Lys(9)-Thr(10)-Phe(11)-Cys(14)-OH (des-AA(1, 2, 4, 5, 12, 13)[Tyr(7), D-Agl(8)(N(beta) Me, 2-naphthoyl)]-SRIF) (peptide 1) has been determined by (1)H NMR in water and molecular dynamics (MD) simulations. The peptide exists in two conformational isomers differing mainly by the cis/trans isomerization of the side chain in residue 8. The structure of 1 is compared with the consensus structural motifs of other somatostatin analogues that bind predominantly to SSTR1, SSTR2/SSTR5 and SSTR4 receptors, and to the 3D structure of a non-selective SRIF analogue, cyclo(3-14)H-Cys(3)-Phe(6)-Tyr(7)-D-2Nal(8)-Lys(9)-Thr(10)-Phe(11)-Cys(14)-OH (des-AA(1, 2, 4, 5, 12, 13)[Tyr(7), D-2Nal(8)]-SRIF) (peptide 2). The structural determinant factors that could explain selectivity of peptide 1 for SSTR3 receptors are discussed.

Amino Acid Sequence↗

PubMed2005

ENPDA: an evolutionary structure-based de novo peptide design algorithm.

One of the goals of computational chemists is to automate the de novo design of bioactive molecules. Despite significant advances in computational approaches to ligand design and binding energy evaluation, novel procedures for ligand design are required. Evolutionary computation provides a new approach to this design endeavor. We propose an evolutionary tool for de novo peptide design, based on the evaluation of energies for peptide binding to a user-defined protein surface patch. Special emphasis has been placed on the evaluation of the proposed peptides, leading to two different evaluation heuristics. The software developed was successfully tested on the design of ligands for the proteins prolyl oligopeptidase, p53, and DNA gyrase.

Algorithms↗

PubMed2005

Design of enhanced agonists through the use of a new virtual screening method: application to peptides that bind class I major histocompatibility complex (MHC) molecules.

A new screening procedure is described that uses docking calculations to design enhanced agonist peptides that bind to major histocompatibility complex (MHC) class I receptors. The screening process proceeds via single mutations of one amino acid at the positions that directly interact with the MHC receptor. The energetic and structural effects of these mutations have been studied using fragments of the original ligand that vary in length. The results of these docking studies indicate that the mutant affinity ranking of long peptides can be practically reproduced with a screening approach performed using fragments of six residues. Fragments of four and five residues could mimic, in some cases, the structural arrangement of the side chains of the full-length peptide. We have compared the structural and energetic results of the docking calculations with experimental data using three unrelated ligand peptides that differ greatly in their affinity for the MHC complex. Analysis of the affinity of the fragments led to the identification of three important parameters in the construction of fragments that mimic the structural and energetic properties of the full-length ligand: the length of the fragment; its intermolecular energy; and the number and localization, internal or terminal, of the anchor residues. The results of this new peptide-design methodology have been applied to suggest new peptides derived from the MUC1-8 peptide that could be used as murine vaccines that trigger the immune response through the MHC class I protein H-2K(b).

Animals↗