Rational design and exploitation of the molecular diversity space of PRX1-derived SRX1 peptidic inhibitors containing proteinogenic and nonproteinogenic amino acids

IF 1.6 4区 化学 Q3 CHEMISTRY, MULTIDISCIPLINARY
Haijin Yang, Ping Li, Yanxin Wan, Rongyuan Qiu, Mengxi Xiao, Zhiyuan Zhu, Xiaoqiong Wu
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引用次数: 0

Abstract

The peroxiredoxin-1 (PRX1) of redox peroxidase reduces reactive oxygen and nitrogen species levels in human cells and can be regulated by its interacting partner sulfiredoxin-1 (SRX1). A 9-mer core peptide segment (termed CTTc) located in the C-terminal tail of PRX1 was found previously to mediate the PRX1–SRX1 interaction, and proteinogenic amino acids were also examined for each residue of the CTTc peptide. However, only proteinogenic amino acids can guarantee sufficient exploitation of the structural diversity space of CTTc-derived peptidic inhibitors targeting SRX1. In this study, the structural diversity space was further expanded by introducing 34 nonproteinogenic amino acids plus 20 proteinogenic amino acids as the building blocks of nonapeptides, and a systematic single-position binding energy change (SSRBEC) profile of the nonapeptide against SRX1 was created computationally by performing machine learning scoring, molecular dynamics simulation, and binding energetics analysis. A reduced combinatorial peptide library consisting of over 500,000 nonproteinogenic amino acid-containing nonapeptide candidates was designed using a rational computational peptidology strategy based on the SSRBEC profile, from which a variety of top-scored hits were identified and their affinities to SRX1 were measured at the molecular level to substantiate the computational findings. Three nonproteinogenic amino acid-containing peptides, CTTc[ut8], CTTc[ut3], and CTTc[ut6] possessed high potency, and their affinities were improved considerably relative to the native CTTc peptide. Structural analysis revealed that the SRX1-binding peptide sequences can be divided into three sections, that is, amino-terminal section N, middle section M, and carboxy-terminal section C, in which section N and, secondarily, section C are primarily responsible for the peptide binding affinity and specificity to SRX1, while section M is exposed to solvent and does not directly interact with SRX1.

Abstract Image

合理设计和利用含有致蛋白氨基酸和非致蛋白氨基酸的 PRX1 衍生 SRX1 肽抑制剂的分子多样性空间
氧化还原过氧化物酶的过氧化物还毒素-1 (PRX1)可降低人体细胞中活性氧和活性氮的水平,并可通过其相互作用伙伴硫氧还毒素-1 (SRX1)进行调节。先前在PRX1的c端尾部发现了一个9-mer核心肽段(称为CTTc),介导PRX1 - srx1相互作用,并且还检测了CTTc肽的每个残基的蛋白原氨基酸。然而,只有蛋白原性氨基酸才能保证cttc衍生的靶向SRX1的肽抑制剂的结构多样性空间得到充分利用。本研究通过引入34种非蛋白原性氨基酸和20种蛋白原性氨基酸作为非肽的构建块,进一步扩大了结构多样性空间,并通过机器学习评分、分子动力学模拟和结合能学分析,计算构建了非肽抗SRX1的系统单位置结合能变化(SSRBEC)谱。利用基于SSRBEC谱的合理计算肽学策略,设计了一个由超过50万个含非蛋白性氨基酸的候选非肽组成的简化组合肽库,从中鉴定出各种得分最高的命中点,并在分子水平上测量它们与SRX1的亲和力,以证实计算结果。CTTc[ut8]、CTTc[ut3]和CTTc[ut6]三种非蛋白性氨基酸肽具有较高的效价,其亲和性较天然CTTc肽有明显提高。结构分析表明,SRX1结合肽序列可分为氨基末端N段、中间M段和羧基末端C段,其中N段和C段主要负责与SRX1的肽结合亲和性和特异性,而M段暴露于溶剂中,不直接与SRX1相互作用。
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来源期刊
CiteScore
3.40
自引率
11.10%
发文量
216
审稿时长
7.5 months
期刊介绍: The Journal of the Chinese Chemical Society was founded by The Chemical Society Located in Taipei in 1954, and is the oldest general chemistry journal in Taiwan. It is strictly peer-reviewed and welcomes review articles, full papers, notes and communications written in English. The scope of the Journal of the Chinese Chemical Society covers all major areas of chemistry: organic chemistry, inorganic chemistry, analytical chemistry, biochemistry, physical chemistry, and materials science.
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