Randomized tree construction algorithm to explore energy landscapes.

In this work, a new method for exploring conformational energy landscapes is described. The method, called transition-rapidly exploring random tree (T-RRT), combines ideas from statistical physics and robot path planning algorithms. A search tree is constructed on the conformational space starting from a given state.

Computational study of the free energy landscape of the miniprotein CLN025 in explicit and implicit solvent.

The prediction capabilities of atomistic simulations of peptides are hampered by different difficulties, including the reliability of force fields, the treatment of the solvent or the adequate sampling of the conformational space. In this work, we have studied the conformational profile of the 10 residue miniprotein CLN025 known to exhibit a β-hairpin in its native state to understand the limitations of implicit methods to describe solvent effects and how these may be compensated by using different force fields. For this purpose, we carried out a thorough sampling of the conformational space of CLN025 in explicit solvent using the replica exchange molecular dynamics method as a sampling technique and compared the results with simulations of the system modeled using the analytical linearized Poisson-Boltzmann (ALPB) method with three different AMBER force fields: parm94, parm96, and parm99SB.

Conformational profile of bombesin assessed using different computational protocols.

The present work involves the study of the conformational profile of bombesin using different computational procedures used to explore the configurational space based on molecular dynamics simulations. Specifically, the present study describes the effect of using Berendsen's versus Langevin's thermostat and on the other hand, the use of the multicanonical replica exchange molecular dynamics as compared to standard molecular dynamics. In these simulations the solvent was modeled using the Onufriev, Bashford and Case implementation of Generalized Born procedure.

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 beta-turn structures in dichloromethane with different type I/type II beta-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.

Molecular dynamics (MD) simulations of VIP and PACAP27.

Vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating polypeptide-27 (PACAP27) are members of the secretin-glucagon family containing 28 and 27 residues, respectively. NMR spectroscopy studies suggest that the N-terminus exhibit consecutive beta-turns whereas the central and C-terminal parts of the VIP molecule have been characterized as being two alpha-helices. In contrast, similar studies carried out on PACAP suggest that the shortest active peptide segment PACAP27 in the presence of trifluoroethanol (TFE) exhibits a disordered N-terminal domain followed by a alpha-helix expanding residues 9-26 with a discontinuity between residues 20 and 21.

Structural analysis of substance P using molecular dynamics and NMR spectroscopy.

The present work is a combined structural study, using Nuclear Magnetic Resonance (NMR) and Molecular Dynamics(MD), of the amidated and the free acid forms of substance P in water and methanol. The results obtained using both approaches were compared in order to characterize the structural features of both peptides in solution. From the NMR experiments it was derived that the free acid form adopts an extended conformation at the N-terminus and a helical conformation at the C-terminal segment of the peptide in both water and methanol; these structural features are in qualitative agreement with the results of the MD simulations.

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.

A theoretical study of pentacyclo-undecane cage peptides of the type [Ac-X-Y-NHMe].

The conformational preferences of peptides of the type, Ac-X-Y-NHMe, where X and Y = Ala, cage and Pro, were studied by means of computational techniques within the framework of a molecular mechanics approach. For each of the eight peptide analogues, extensive conformational searches were carried out using molecular dynamics (MD) and simulated annealing (SA) protocols in an iterative fashion. Both results are in good agreement and complement each other.

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.

Molecular modeling in the design of peptidomimetics and peptide surrogates.

The most important natural sources of new leads are plant extracts, bacterial broths, animal venoms and peptides isolated from living organisms. However, only the three first have been used extensively in the development of new therapeutic agents. This is probably due to the low pharmacological profile exhibited by peptides, that requires a lengthy transformation to make them suitable as new leads.

Identification of selective inhibitors of acetylcholinesterase from a combinatorial library of 2,5-piperazinediones.

The potentiation of central cholinergic activity has been proposed as a therapeutic approach for improving cognitive function in patients with Alzheimer's disease. Increasing the acetylcholine concentration in brain by modulating acetylcholinesterase (AChE) activity is among the most promising strategies. We have used a combinatorial approach to identify different 2,5-piperazinediones (DKP) with AChE inhibitory activity.

Docking of peptide-T onto the D1 domain of the CD4 receptor.

Peptide T (pepT) is a segment of the human immunodeficiency virus (HIV) envelope protein gp120. The peptide competitively binds to the CD4 receptor of a subset of peripheral T lymphocytes and inhibits binding of gp120. Previous studies of this laboratory allowed the assessment of a bioactive form of the peptide and a pharmacophore for the peptide-receptor interaction.

Assessment of the bioactive conformation of the farnesyltransferase protein binding recognition motif by computational methods.

Ras farnesyltransferase catalyzes the carboxyl-terminal farnesylation of Ras as well as other proteins involved in signal transduction processes. Previous studies demonstrated that its inhibition suppresses the activity of Ras transformed phenotypes in cultured cells, causing tumor regression in animal models. This observation led to the consideration of farnesyltransferase as a target for cancer therapy.