Biology subjects

Stratmann, D.

Publications and source records attributed to Stratmann, D..

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↗

bioRxiv2024

Simulated Solute Tempering 2

Molecular dynamics (MD) simulations are powerful tools for studying the movement and interactions of molecules, but they can be computationally expensive, especially for large biomolecules like proteins. This is problematic because accurately simulating the motions of these molecules is key to understanding their function. Enhanced sampling methods, such as Simulated Tempering (ST), temperature Replica Exchange Molecular Dynamics (REMD) and Replica Exchange with Solute Tempering (REST and REST2), have been developed to overcome this challenge by improving the efficiency of MD simulations. This article presents a new enhanced sampling method called Simulated Solute Tempering 2 (SST2) that builds upon the strengths of ST and REST2. SST2 selectively scales the interactions inside a biomolecule and with its surrounding environment, effectively accelerating the exploration of its different structural states and their stability at various temperatures. SST2 was tested on three different systems (chignolin CLN025, Trp-Cage, and a protein-peptide complex, p97/PNGase) and found to achieve comparable or superior sampling efficiency to ST, SST1 and REST2 while requiring fewer temperature rungs. Notably, SST2 is particularly well-suited for investigating large biomolecular systems, making it a valuable tool for studying a wide range of biomolecular processes, from protein folding to ligand binding. Significance StatementAccurately simulating the motions of biological molecules like proteins is key to understanding their function. However, this is computationally expensive, especially for large systems or slow processes. To overcome this, we developed Simulated Solute Tempering 2 (SST2), a novel algorithm that improves the efficiency of molecular dynamics (MD) simulations. SST2 selectively scales the interactions inside a biomolecule and with its surrounding environment, accelerating the exploration of its different structures and their stability at various temperatures. This allows SST2 to achieve remarkable performances with a clear improved ease of use compare to similar methods, particularly for large systems like protein-ligand complexes. This makes SST2 a valuable tool for studying a wide range of biomolecular processes, from protein folding to ligand binding. TOC Graphic O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=111 SRC="FIGDIR/small/613476v3_ufig1.gif" ALT="Figure 1"> View larger version (41K): org.highwire.dtl.DTLVardef@761755org.highwire.dtl.DTLVardef@f5df1forg.highwire.dtl.DTLVardef@ba93dorg.highwire.dtl.DTLVardef@193e7eb_HPS_FORMAT_FIGEXP M_FIG C_FIG

biophysics↗

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↗