Josep Canto

Complete maps of molecular‐loop conformational spaces

This paper presents a numerical method to compute all possible conformations of distance‐constrained molecular loops, i.e., loops where some interatomic distances are held fixed, while others can vary. The method is general (it can be applied to single or multiple intermingled loops of arbitrary topology) and complete (it isolates all solutions, even if they form positive‐dimensional sets). Generality is achieved by reducing the problem to finding all embeddings of a set of points constrained by pairwise distances, which can be formulated as computing the roots of a system of Cayley–Menger determinants. Completeness is achieved by expressing these determinants in Bernstein form and using a numerical algorithm that exploits such form to bound all root locations at any desired precision. The method is readily parallelizable, and the current implementation can be run on single‐ or multiprocessor machines. Experiments are included that show the methods performance on rigid loops, mobile loops, and multiloop molecules. In all cases, complete maps including all possible conformations are obtained, thus allowing an exhaustive analysis and visualization of all pseudo‐rotation paths between different conformations satisfying loop closure.

Conformational behavior of the HAV-VP3(110–121) peptidic sequence and synthetic analogs in membrane environments studied by CD and computational methods

The present study was undertaken to examine the structural features that may be important to explain the immunogenicity of the (110-121) peptide sequence (FWRGDLVFDFQV) of VP3 capsid protein of hepatitis A virus. A conformational analysis of the preferred conformations by CD and molecular mechanics was carried out. Present results suggest that the interaction with liposomes as biomembrane model induces and stabilizes the amphipathic beta-structure of the peptide. To study the contribution of amino acid replacements at the RGD tripeptide as well as the influence of the peptide chain length on peptide conformation, solid-phase peptide synthesis of several peptide analogs was carried out and the peptide conformation was studied using CD spectroscopy. The results show that the RGD sequence is necessary to induce the beta-structure in the presence of liposomes.

Comparative analysis of the conformational profile of substance P using simulated annealing and molecular dynamics

The present study describes an extensive conformational search of substance P using two different computational methods. On the one hand, the peptide was studied using the iterative simulated annealing, and on the other, molecular dynamics simulations at 300 and 400 K. With the former method, the peptide was studied in vacuo with a dielectric constant of 80, whereas using the latter study the peptide was studied in a box of TIP3P water molecules. Analysis of the results obtained using both methodologies was carried out using an in‐house methodology using a cluster analysis method based on information theory. Comparison of the two sampling methodologies and the different environment used in the calculations is also analyzed. Finally, the conformational motifs that are characteristic of substance P in a hydrophilic environment are presented and compared with the experimental results available in the literature.

Conformational study of the preferred conformations of the peptide sequence VP3(110–121) of HAV by circular dichroism and molecular mechanics

A conformational analysis of the fragment 110–121 of VP3 coating protein of the hepatitis A virus was carried out using circular dichroism spectroscopy and computational studies. The latter studies indicate the tendency of the peptide to adopt hairpin-type structures. Circular dichroism experiments indicate that, in spite of the fact that the isolated peptide exhibits no structure under different experimental conditions, negatively charged liposomes induce a secondary structure that agrees with the results of the computational study.

Conformational study of the pentadecapeptide 2F10 by circular dichroism, IR spectroscopy and molecular mechanics

The conformational profile of the pentadecapeptide of sequenceAVYYCTRGYHGSSLY, capable of mimicking the group-specific ‘a’ determinant of human hepatitis B surface antigen at both the B- and T-cell level, was assessed using the combined informationprovided by circular dichroism (CD) studies, IR spectroscopy and molecular mechanics. Specifically, the CD spectra of the peptide was recorded in various environments including an aqueous buffer, trifluoroethanol, hexafluoroisopropanol and inmicellar solutions of sodium dodecylsulfate in order to analyzeits conformational profile. Analysis of the results suggests the strong tendency of the peptide to adopt β structures in the different structuring media. Furthermore, the IR spectrumof the peptide recorded in DMSO shows absorptions compatible with a β sheet structure. Finally, molecular mechanics calculations using an iterative simulated annealing protocol to sample the conformational space, supplemented by a moleculardynamics simulation in water, suggest as the most important peptide secondary structure feature the adoption of a hairpinconformation. Accordingly, the combined information provided by the different techniques used in the present work, consistently suggest that the peptide 2F10 exhibits a tendencyto adopt a hairpin conformation in solution.

Molecular dynamics study of kaliotoxin in water

Kaliotoxin (KTX), a potassium channel blocker found in the venom of the scorpion Androctonous Mauretanicus is a 38 residue polypeptide with a well defined structure consisting of a alpha-helix and a three strand antiparallel beta-sheet interconnected by three disulfide bonds. Although the 3D structure has been determined by NMR, there is a number of features, mainly concerning the conformation and flexibility of the side chains, but also the long range order in the peptide and its fluctuations, that may have escaped the experimental study. These questions are now being addressed using molecular dynamics (MD) simulations. Accordingly, the present work reports the analysis of a 430 ps molecular dynamics trajectory of the polypeptide soaked with 4700 TIP3 water molecules inside a 56 A box. MD calculations were performed with periodic boundary conditions. Analysis of the conformational space sampled by each of the residues along the trajectory, suggests a special behavior of Pro17 and Lys19 both located on the helix. Furthermore, analysis of the relative movements of the secondary structure elements indicates that the alpha-helix and beta-sheets fluctuate in a correlated motion, preserving the tertiary structure of the polypeptide along the trajectory. Finally, analysis of the charge distribution was also examined. The direction of the dipole moment, computed from the center of masses appears to be an interesting feature of the structure probably related to the biological function of the molecule.

Computational investigation of the conformational profile of the four stereomers of Ac-L-Pro-c3Phe-NHMe (c3Phe= 2,3-methanophenylalanine).

The present report regards a computational study aimed at assessing the conformational profile of the four stereoisomers of the peptide Ace‐Pro‐c3Phe‐NMe, previously reported to exhibit β‐turn structures in dichloromethane with different type I/type II β‐turn profiles. Molecular systems were represented at the molecular mechanics level using the parm96 parameterization of the AMBER force field. Calculations were carried out in dichloromethane using an implicit solvent approach. Characterization of the conformational features of the peptide analogs was carried out using simulated annealing (SA), molecular dynamics (MD) and replica exchange molecular dynamics (REMD). Present results show that MD calculations do not provide a reasonable sampling after 300 ns. In contrast, both SA and REMD provide similar results and agree well with experimental observations.