Toward accurately modeling N-methylated cyclic peptides

Abstract

Cyclic peptides have unique properties and can target protein surfaces specifically and potently. N-Methylation provides a promising way to further optimize the pharmacokinetic and structural profiles of cyclic peptides. The capability to accurately model structures adopted by N-methylated cyclic peptides would facilitate rational design of this interesting and useful class of molecules. We apply molecular dynamics simulations with advanced enhanced sampling methods to efficiently characterize the structural ensembles of N-methylated cyclic peptides, while simultaneously evaluating the overall performance of several simulation force fields. We find that one of the residue-specific force fields, RSFF2, is able to recapitulate experimental structures of the N-methylated cyclic peptide benchmarks tested here when the correct amide isomers are used as initial configurations and enforced during the simulations. Thus, using our simulation approach, it is possible to accurately and efficiently predict the structures of N-methylated cyclic peptides if sufficient information is available to determine the correct amide cis/trans configuration. Moreover, our results suggest that, upon further optimization of RSFF2 to more reliably predict cis/trans isomers, molecular dynamics simulations will be able to de novo predict N-methylated cyclic peptides in the near future, strongly motivating such continued optimization.

Peptidic Macrocycles - Conformational Sampling and Thermodynamic Characterization

“… 32 Also other force-field-based studies applying enhanced sampling techniques, such as metadynamics 33 , 34 and replica-exchange MD, 35 to characterize the structural ensemble of cyclic peptides showed highly promising results. 36 − 38 …”

β-Branched Amino Acids Stabilize Specific Conformations of Cyclic Hexapeptides

“…We found that for small CPs, two dihedral angles, either the f and j angles of the same residue (f i and j i ) or the j angle of one residue and the f angle of the next residue (j i and f iþ1 ), need to change coherently to enable conformational switches. By targeting these essential transitional motions using bias-exchange metadynamics (BE-META) simulations, we can efficiently sample the conformational space of a CP (22)(23)(24). Using this method, we started examining CP sequence-structure relationships with explicit-water molecular dynamics (MD) simulations by gradually substituting Gly residues in cyclo-(GGGGGG) with Val.…”

Understanding and designing head‐to‐tail cyclic peptides

“…One of these template structures, cyclo‐(aAAAAA) (underlines indicate N ‐methylated residues), contained all trans peptide bonds and two type II β‐turns at residues 6 Aa 1 and 3 AA 4 in DMSO (Figure A). When simulated with explicit DMSO molecules, the simulation results accurately recapitulated the NMR structure (Figure B) . However, this is not the case when simulated with implicit solvent using a dielectric constant equivalent to DMSO ( ɛ = 47) (Figure C).…”

“…Therefore, it remains to be tested whether RSFF2 can successfully predict solution structures of CPs, or those CPs containing cis peptide bonds and/or non‐natural amino acids. In a recent study, it was shown that RSFF2 was not capable of reliably predicting the cis / trans isomers of simple N ‐methylated cyclic hexapeptides . Further optimization of the force field to describe the ratio between the cis and trans conformations is thus required if de novo structure prediction including the cis / trans isomer state is desired.…”