Predicting the conformational states of cyclic tetrapeptides

Abstract

Biologically active cyclic tetrapeptides, usually found among fungi metabolites, exhibit phytotoxic or cytostatic activities that are likely to be governed by specific conformations adopted in solution. For conformational studies and drug design, there is a strong interest in using fast and reliable methods to determine correctly the conformational population of cyclotetrapeptides. We show here that standard molecular mechanics computational approach gives satisfactory results. The method was validated step by step by experimental data either obtained after synthesis and NMR analysis, or found in the literature. The cyclo(Gly)(4), cyclo(Ala)(4), cyclo(Sar)(4), and cyclo(SarGly)(2) peptides were used to evaluate the prediction of the peptide backbone conformation, and the detailed conformational analysis of tentoxin, a natural phytotoxic cyclotetrapeptide in which N-alkylated peptide bonds alternate with regular secondary ones, was used to validate the computation of conformers proportions. From the knowledge of an initial cyclic primary structure and of the D or L configuration of the amino acids, we show that it is possible to determine the exact orientation of carbonyl groups and to predict the nature of conformers present in solution. The proportion of each conformer can be inferred from a statistical thermodynamics approach by using the potential energy values of each conformer, computed by molecular mechanics methods with the TRIPOS force field, which allowed us to account for the solvent. The solvent contribution was processed by two different methods according to the nature of the interactions: whether through the dielectric constant introduced in the electrostatic potential, when interaction with solute molecules are weak or negligible, or through the computation of free energy of solvation using the algorithm SILVERWARE for solvents explicitly interacting with the solute. When applied to tentoxin, this conformational analysis yielded results in very good agreement with the experimental data reported by Pinet et al. (Biopolymers, 1995, Vol. 36, pp. 135-152), on both the nature of existing conformers and their relative proportions, whatever the nature of the considered solvent.

Naturally-Occurring Cyclopeptides: Structures and Bioactivity

“…Standard molecular mechanics computational approach gave satisfactory results [310]. From the knowledge of an initial cyclic primary structure and of the D or L configuration of the amino acids, it was possible to determine the exact orientation of carbonyl groups and to predict the nature of conformers present in solution The proportion of each conformer could be inferred from a statistical thermodynamic approach by using the potential energy values of each conformer, computed by molecular mechanics methods, which allowed to account for the solvent.…”

“…From the knowledge of an initial cyclic primary structure and of the D or L configuration of the amino acids, it was possible to determine the exact orientation of carbonyl groups and to predict the nature of conformers present in solution The proportion of each conformer could be inferred from a statistical thermodynamic approach by using the potential energy values of each conformer, computed by molecular mechanics methods, which allowed to account for the solvent. The solvent contribution was processed by two different methods according to the nature of the interactions: whether through the dielectric constant introduced in the electrostatic potential, when interaction with solute molecules was weak or negligible, or through the computation of free energy of solvation using the algorithm for solvents explicitly interacting with the solute [310].…”

c[D‐pro‐Pro‐D‐pro‐N‐methyl‐Ala] adopts a rigid conformation that serves as a scaffold to mimic reverse‐turns

“…CTPs macrocycles tend to either a boat or chair conformation, in a similar fashion to cyclohexane. 26,27 To use CTPs as effective turn mimics, this boat or chair conformation must be known. In addition the various macrocycles have different dipoles that might impact binding to different receptors.…”

“…The CTP c[Pro-proPro-pro] is a combination of these two reverse-turn mimetic approaches shown to exist with stable cis-trans-cis-trans and trans-cis-trans-cis amide bond conformers at room temperature in water. 25,26 In this study, we modified the CTP c[Propro-Pro-pro] by substituting L-or D-proline with alanine, Nmethyl-alanine (NMe-Ala), or L-or D-pipecolic acid (Pip) to stabilize other sets of amide conformations such as transtrans-trans-trans and trans-trans-cis-trans. Different sequences of amide-bond torsions, which dictates the backbonering conformations, changes the relative orientation of the proline and Pip rings enabling them to act as mimics for multiple turn types.…”

Exploring the conformational space of cyclic peptides by a stochastic search method

“…There is much interest in predicting the conformational space of cyclic peptides, and some approaches have been successful in finding the global minimum or closely related structures [41,[47][48][49][50]. Currently, the conformational search of cyclic peptides is performed with a variety of methods or protocols.…”