Peptidic Macrocycles - Conformational Sampling and Thermodynamic Characterization.

Anna S. Kamenik,Uta Lessel,Thomas Fox,Klaus R. Liedl,Julian E. Fuchs

doi:10.1021/acs.jcim.8b00097

Abstract

Macrocycles are of considerable interest as highly specific drug candidates, yet they challenge standard conformer generators with their large number of rotatable bonds and conformational restrictions. Here, we present a molecular dynamics-based routine that bypasses current limitations in conformational sampling and extensively profiles the free energy landscape of peptidic macrocycles in solution. We perform accelerated molecular dynamics simulations to capture a diverse conformational ensemble. By applying an energetic cutoff, followed by geometric clustering, we demonstrate the striking robustness and efficiency of the approach in identifying highly populated conformational states of cyclic peptides. The resulting structural and thermodynamic information is benchmarked against interproton distances from NMR experiments and conformational states identified by X-ray crystallography. Using three different model systems of varying size and flexibility, we show that the method reliably reproduces experimentally determined structural ensembles and is capable of identifying key conformational states that include the bioactive conformation. Thus, the described approach is a robust method to generate conformations of peptidic macrocycles and holds promise for structure-based drug design.

Highlights

Macrocycles are an intriguing compound class, as they promise to address long-standing druggability challenges such as protein−protein interfaces with remarkably high affinity.[1−3] Especially peptidic macrocycles show significantly increased activity and bioavailability compared to their acyclic counterparts.[4]
We found that including only snapshots with high boosting potentials consistently leads to cluster representatives that are located near the free energy minima in principal component analysis (PCA) space
We evaluated the performance of explicit solvent accelerated molecular dynamics (aMD)

Summary

Introduction

The striking affinity enhancement due to macrocyclization, which has been observed repeatedly, is proposed to originate from a structural preorganization:[6−8] In macrocyclic compounds, the ring closure reduces the accessible conformational states which ideally would be able stabilize the peptide in its bioactive conformations. Following the concept of conformational selection, this shift of state populations toward the active state favors binding.[9] in case the macrocyclization stabilizes a nonbioactive conformational state in solution, it could slow down binding. The conformational restraints decrease the loss in conformational entropy upon binding, which contributes to the increased affinities found for macrocyclic compounds.[10]

Methods

Results

Discussion

Conclusion