Thiazole\u2013amino acids: influence of thiazole ring on conformational properties of amino acid residues

Monika Staś,Małgorzata A Broda,Dawid Siodłak

doi:10.1007/s00726-021-02974-0

Abstract

Post-translational modified thiazole–amino acid (Xaa–Tzl) residues have been found in macrocyclic peptides (e.g., thiopeptides and cyanobactins), which mostly inhibit protein synthesis in Gram + bacteria. Conformational study of the series of model compounds containing this structural motif with alanine, dehydroalanine, dehydrobutyrine and dehydrophenylalanine were performed using DFT method in various environments. The solid-state crystal structure conformations of thiazole–amino acid residues retrieved from the Cambridge Structural Database were also analysed. The studied structural units tend to adopt the unique semi-extended β2 conformation; which is stabilised mainly by N–H⋯NTzl hydrogen bond, and for dehydroamino acids also by π-electron conjugation. The conformational preferences of amino acids with a thiazole ring were compared with oxazole analogues and the role of the sulfur atom in stabilising the conformations of studied peptides was discussed.

Highlights

The biological activity and metal-binding properties of proteins and peptides depend on their conformation (Giri Rao and Gosavi 2016)
The aim of this work is to provide an in-depth analysis of conformational properties of thiazole-containing amino acids (Xaa–Tzl), where the thiazole ring is in place of the C-terminal amide group (Fig. 1)
Its population is quite high, around 79%. The stability of this conformation can be explained by the presence of intramolecular hydrogen bonds; N–H⋯NTZL formed between the hydrogen atom of amide group and the nitrogen atom of thiazole ring as well as Cα–H⋯O hydrogen bond created by the hydrogen atom of α carbon atom and the oxygen atom of amide group

Summary

Introduction

The biological activity and metal-binding properties of proteins and peptides depend on their conformation (Giri Rao and Gosavi 2016). The capability of changing ligand conformation to improve binding affinity in proteins is one of the biomolecular engineering tools crucial for drug discovery and design (Lassila 2010; Gagné et al 2012; Boehr et al 2018; Ding et al 2020; Aguesseau-Kondrotas et al 2019). Mapping the conformational space of small peptide fragments is an important prerequisite in decoding the protein folding process and understanding protein structure

Objectives

Results

Conclusion