The necessity of d-Thr in the new antibiotic teixobactin : a molecular dynamics study

Ever since the discovery of the new antibiotic teixobactin, studies of its structure–activity relationships have never ceased. Here we focus on the chirality of the threonine (Thr) residue, which belongs to the ring motif of teixobactin and plays an important role in the binding with its target, lip...

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Main Authors:	Liu, Yang, Li, Weifeng, Chan-Park, Mary B., Mu, Yuguang
Other Authors:	School of Chemical and Biomedical Engineering
Format:	Article
Language:	English
Published:	2020
Subjects:	Science::Biological sciences Chirality Lipids
Online Access:	https://hdl.handle.net/10356/144892
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Institution:	Nanyang Technological University
Language:	English

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spelling	sg-ntu-dr.10356-1448922023-12-29T06:47:11Z The necessity of d-Thr in the new antibiotic teixobactin : a molecular dynamics study Liu, Yang Li, Weifeng Chan-Park, Mary B. Mu, Yuguang School of Chemical and Biomedical Engineering School of Biological Sciences Centre for Antimicrobial Bioengineering Science::Biological sciences Chirality Lipids Ever since the discovery of the new antibiotic teixobactin, studies of its structure–activity relationships have never ceased. Here we focus on the chirality of the threonine (Thr) residue, which belongs to the ring motif of teixobactin and plays an important role in the binding with its target, lipid II molecule. We study the structural propensity of the open and closed ring motifs with different chiral Thr residues as well as the teixobactin–lipid II complex with the help of molecular dynamics simulations. Our results suggest that different chiralities lead to different NH orientations of Thr with respect to the ring plane. Only in the closed ring motif with d-Thr is a favored binding cavity achievable with all four NH groups facing the same side of the ring plane. This study develops a deeper understanding of the binding mechanism of teixobactin and lipid II and is expected to be beneficial to new teixobactin-based drug design. National Medical Research Council (NMRC) National Supercomputing Centre (NSCC) Singapore Accepted version We are grateful for financial support from a Singapore Ministry of Education Academic Research Fund Tier 3 Grant (MOE2013-T3-1-002), the Singapore Ministry of Health Industry Alignment Fund (NMRC/MOHIAFCAT2/003/2014), and an MOE Tier 1 Grant (RG 146/17). We also thank the National Supercomputing Centre (NSCC), Singapore, for providing computational resources. Y.L. acknowledges the support of Ph.D. Research Scholarships from MOE. 2020-12-02T06:56:32Z 2020-12-02T06:56:32Z 2019 Journal Article Liu, Y., Li, W., Chan-Park, M. B., & Mu, Y. (2019). The Necessity of d-Thr in the New Antibiotic Teixobactin: A Molecular Dynamics Study. Journal of Chemical Information and Modeling, 59(4), 1575–1583. doi:10.1021/acs.jcim.8b00949 1549-9596 https://hdl.handle.net/10356/144892 10.1021/acs.jcim.8b00949 4 59 1575 1583 en Journal of Chemical Information and Modeling This document is the Accepted Manuscript version of a Published Work that appeared in final form in Journal of Chemical Information and Modeling, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see https://doi.org/10.1021/acs.jcim.8b00949 application/pdf
institution	Nanyang Technological University
building	NTU Library
continent	Asia
country	Singapore Singapore
content_provider	NTU Library
collection	DR-NTU
language	English
topic	Science::Biological sciences Chirality Lipids
spellingShingle	Science::Biological sciences Chirality Lipids Liu, Yang Li, Weifeng Chan-Park, Mary B. Mu, Yuguang The necessity of d-Thr in the new antibiotic teixobactin : a molecular dynamics study
description	Ever since the discovery of the new antibiotic teixobactin, studies of its structure–activity relationships have never ceased. Here we focus on the chirality of the threonine (Thr) residue, which belongs to the ring motif of teixobactin and plays an important role in the binding with its target, lipid II molecule. We study the structural propensity of the open and closed ring motifs with different chiral Thr residues as well as the teixobactin–lipid II complex with the help of molecular dynamics simulations. Our results suggest that different chiralities lead to different NH orientations of Thr with respect to the ring plane. Only in the closed ring motif with d-Thr is a favored binding cavity achievable with all four NH groups facing the same side of the ring plane. This study develops a deeper understanding of the binding mechanism of teixobactin and lipid II and is expected to be beneficial to new teixobactin-based drug design.
author2	School of Chemical and Biomedical Engineering
author_facet	School of Chemical and Biomedical Engineering Liu, Yang Li, Weifeng Chan-Park, Mary B. Mu, Yuguang
format	Article
author	Liu, Yang Li, Weifeng Chan-Park, Mary B. Mu, Yuguang
author_sort	Liu, Yang
title	The necessity of d-Thr in the new antibiotic teixobactin : a molecular dynamics study
title_short	The necessity of d-Thr in the new antibiotic teixobactin : a molecular dynamics study
title_full	The necessity of d-Thr in the new antibiotic teixobactin : a molecular dynamics study
title_fullStr	The necessity of d-Thr in the new antibiotic teixobactin : a molecular dynamics study
title_full_unstemmed	The necessity of d-Thr in the new antibiotic teixobactin : a molecular dynamics study
title_sort	necessity of d-thr in the new antibiotic teixobactin : a molecular dynamics study
publishDate	2020
url	https://hdl.handle.net/10356/144892
_version_	1787136502295166976

The necessity of d-Thr in the new antibiotic teixobactin : a molecular dynamics study

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