Biology subjects

Chomilier, J.

Publications and source records attributed to Chomilier, J..

3 recordsLinked to original sources

bioRxiv2025

Robust conformational space exploration of cyclic peptides by combining different MD protocols and force fields

Cyclic peptides are an important class of pharmaceutical drugs. We used here replica-exchange molecular dynamics (REMD) and simulated tempering (ST) simulations to explore the conformational landscape of a set of nine cyclic peptides. The N-ter to C-ter backbone cyclized peptides of seven to ten residues were previously designed for a high conformational stability with a mixture of L and D amino acids. Their experimental NMR structures were available in the protein data bank (PDB). For each peptide we tested several force fields, Amber96, Amber14, RSFF2C and Charmm36m in implicit and explicit solvent. We find that the variability of the free energy maps obtained from several protocols is larger than the variability obtained by just repeating the same protocol. Running multiple protocols is therefore important for the convergence assessment of REMD or ST simulations. The majority of the free energy maps showed clusters with a high RMSD to the native structures, revealing the residual flexibility of this set of cyclic peptides. The high RMSD clusters had in some cases the lowest free energy, rendering the prediction of the native structure more difficult with a single protocol. Fortunately, the combination of four implicit solvent REMD and ST simulations, mixing the Amber96 and Am-ber14 force fields, predicted robustly the native structure. As implicit solvent in the REMD or ST setup are up to one hundred times faster than explicit solvent simulations, so running four implicit solvent simulations is a good practical choice. We checked that the use of an explicit solvent REMD or ST simulation, taken alone or combined with implicit solvent simulations, did not significantly improved our results. It results that our combination of four implicit solvent simulations is tied in terms of success rate with much more expensive combinations that include explicit solvent simulations. This may be used as guideline for further studies of cyclic peptide conformations.

biophysics↗

bioRxiv2018

Protein Multiple Alignments: Sequence-based vs Structure-based Programs

Facing the huge increase of information about proteins, classification has reached the level of a compulsory task, essential for assigning a function to a given sequence, by means of comparison to existing data. Multiple sequence alignment programs have been proven to be very useful and they have already been evaluated. In this paper we wished to evaluate the added value provided by taking into account structures. We compared the multiple alignments resulting from 24 programs, either based on sequence, structure, or both, to reference alignments deposited in five databases. Reference databases, on their side, can be split in two: more automatic ones, and more manually ones. Scores have been attributed to each program. As a global rule of thumb, five groups of methods emerge, with the lead to two of the structure-based programs. This advantage is increased at low levels of sequence identity among aligned proteins, or for residues in regular secondary structures or buried. Concerning gap management, sequence-based programs place less gaps than structure-based programs. Concerning the databases, the alignments from the manually built databases are the more challenging for the programs.

bioinformatics↗

bioRxiv2018

Exhaustive exploration of the conformational landscape of small cyclic peptides using a robotics approach

Small cyclic peptides represent a promising class of therapeutic molecules with unique chemical properties. However, the poor knowledge of their structural characteristics makes their computational design and structure prediction a real challenge. In order to better describe their conformational space, we developed a method, named EGSCyP, for the exhaustive exploration of the energy landscape of small head-to-tail cyclic peptides. The method can be summarized by (i) a global exploration of the conformational space based on a mechanistic representation of the peptide and the use of robotics-based algorithms to deal with the closure constraint, (ii) an all-atom refinement of the obtained conformations. EGSCyP can handle D-form residues and N-methylations. Two strategies for the side-chains placement were implemented and compared. To validate our approach, we applied it to a set of three variants of cyclic RGDFV pentapeptides, including the drug candidate Cilengitide. A comparative analysis was made with respect to replica exchange molecular dynamics simulations in implicit solvent. It results that the EGSCyP method provides a very complete characterization of the conformational space of small cyclic pentapeptides.\n\nO_FIG_DISPLAY_L [Figure 1] M_FIG_DISPLAY C_FIG_DISPLAY\n\nThe paper presents a new method for the exhaustive exploration of the conformational energy landscape of small head-to-tail cyclic peptides. The approach is based on a multilevel representation of the peptide and the use of robotics-inspired algorithms.

bioinformatics↗