Elucidating Solution Structures of Cyclic Peptides Using Molecular Dynamics Simulations

Abstract

Protein−protein interactions are vital to biological processes, but the shape and size of their interfaces make them hard to target using small molecules. Cyclic peptides have shown promise as protein−protein interaction modulators, as they can bind protein surfaces with high affinity and specificity. Dozens of cyclic peptides are already FDA approved, and many more are in various stages of development as immunosuppressants, antibiotics, antivirals, or anticancer drugs. However, most cyclic peptide drugs so far have been natural products or derivatives thereof, with de novo design having proven challenging.A key obstacle is structural characterization: cyclic peptides frequently adopt multiple conformations in solution, which are difficult to resolve using techniques like NMR spectroscopy. The lack of solution structural information prevents a thorough understanding of cyclic peptides' sequence−structure−function relationship. Here we review recent development and application of molecular dynamics simulations with enhanced sampling to studying the solution structures of cyclic peptides. We describe novel computational methods capable of sampling cyclic peptides' conformational space and provide examples of computational studies that relate peptides' sequence and structure to biological activity. We demonstrate that molecular dynamics simulations have grown from an explanatory technique to a full-fledged tool for systematic studies at the forefront of cyclic peptide therapeutic design.

Conformational preferences induced by cyclization in orbitides: a vibrational CD study

“…Therefore, correctly assessing the conformational preferences of orbitides and their linear analogues in solution is of paramount importance to understand their bioactivity. Since linear and cyclic peptides frequently adopt multiple conformations in solution, which are difficult to resolve using NMR, 13 their configurational and conformational studies represent an important bottleneck for medicinal chemistry applications. It becomes even more critical as the number of residues increases.…”

Application of per-Residue Energy Decomposition to Design Peptide Inhibitors of PSD95 GK Domain

“…Molecular dynamics (MD) simulation studies have successfully assisted the development of many novel peptides against various drug targets ( Taylor and Jayaraman, 2020 ; Aronica et al, 2021 ; Damjanovic et al, 2021 ). MD simulations facilitate researchers to investigate the interactions of desired biological targets in terms of the binding energies at decreasing costs with advanced simulation methods ( Veselovsky and Ivanov, 2003 ; Aminpour et al, 2019 ).…”

Improved Recovery and Selectivity of Lanthanide-Ion-Binding Cyclic Peptide Hosts by Changing the Position of Acidic Amino Acids

“…More recently, cyclic peptide structure prediction using machine learning has been expected as a future screening/prediction method [32]. The simulation of the solution structure of peptides [33] and the solvent extraction of lanthanide ions [34] have also been reported.…”