Issue 41, 2023

Dynamic geometry design of cyclic peptide architectures for RNA structure

Abstract

Designing inhibitors for RNA is still challenging due to the bottleneck of maintaining the binding interaction of inhibitor-RNA accompanied by subtle RNA flexibility. Thus, the current approach usually needs to screen thousands of candidate inhibitors for binding. Here, we propose a dynamic geometry design approach to enrich the hits with only a tiny pool of designed geometrically compatible scaffold candidates. First, our method uses graph-based tree decomposition to explore the complementarity rigid binding cyclic peptide and design the amino acid side chain length and charge to fit the RNA pocket. Then, we perform an energy-based dynamical network algorithm to optimize the inhibitor-RNA hydrogen bonds. Dynamic geometry-guided design yields successful inhibitors with low micromolar binding affinity scaffolds and experimentally competes with the natural RNA chaperone. The results indicate that the dynamic geometry method yields higher efficiency and accuracy than traditional methods. The strategy could be further optimized to design the length and chirality by adopting nonstandard amino acids and facilitating RNA engineering for biological or medical applications.

Graphical abstract: Dynamic geometry design of cyclic peptide architectures for RNA structure

Supplementary files

Article information

Article type
Paper
Submitted
17 Jul 2023
Accepted
14 Sep 2023
First published
15 Sep 2023

Phys. Chem. Chem. Phys., 2023,25, 27967-27980

Dynamic geometry design of cyclic peptide architectures for RNA structure

S. Ning, M. Sun, X. Dong, A. Li, C. Zeng, M. Liu, Z. Gong and Y. Zhao, Phys. Chem. Chem. Phys., 2023, 25, 27967 DOI: 10.1039/D3CP03384H

To request permission to reproduce material from this article, please go to the Copyright Clearance Center request page.

If you are an author contributing to an RSC publication, you do not need to request permission provided correct acknowledgement is given.

If you are the author of this article, you do not need to request permission to reproduce figures and diagrams provided correct acknowledgement is given. If you want to reproduce the whole article in a third-party publication (excluding your thesis/dissertation for which permission is not required) please go to the Copyright Clearance Center request page.

Read more about how to correctly acknowledge RSC content.

Social activity

Spotlight

Advertisements