结合机器学习优化、分子动力学模拟、结合能重测定和体外亲和力测定,合理设计内分泌Snk PBD结构域的强效磷酸肽结合物。

IF 2.2 4区 生物学 Q3 BIOPHYSICS
Zhaohui Wang, Jixiao Lan, Yan Feng, Yumei Chen, Meiyuan Chen
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引用次数: 0

摘要

人类Snk是一种进化上保守的丝氨酸/苏氨酸激酶,对维持内分泌稳定至关重要。该蛋白由n端催化结构域和c端polo-box结构域(PBD)组成,该结构域决定亚细胞定位和底物特异性。本文采用机器学习建模、退火优化、动力学模拟和能量学评分等综合策略,在分子水平上探索Snk PBD结合磷酸化肽的巨大结构多样性空间,重点研究Snk PBD结构域的识别特异性和基序偏好。我们进一步根据收集到的知识对该结构域的有效磷酸肽配体进行了系统的合理设计,其中一些有效的结合物也通过基于荧光的测定得到了证实。设计了一个磷酸肽PP17作为一个良好的结合物,其亲和力比对照PP0提高了6.7倍,而其他三个设计的磷酸肽PP7、PP13和PP15的效价与PP0相当。此外,我们还定义了一个基本的识别基序,将Snk pbd结合序列划分为四个残基块,即[Χ-5Χ-4]block1-[Ω-3Ω-2Ω-1]block2-[pS0/pT0]block3-[Ψ+1]block4,其中X表示任意氨基酸,Ω表示极性氨基酸,Ψ表示疏水氨基酸,pS0/pT0表示参考残基位置0的锚定磷酸丝氨酸/磷酸苏氨酸。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Rational design of potent phosphopeptide binders to endocrine Snk PBD domain by integrating machine learning optimization, molecular dynamics simulation, binding energetics rescoring, and in vitro affinity assay

Rational design of potent phosphopeptide binders to endocrine Snk PBD domain by integrating machine learning optimization, molecular dynamics simulation, binding energetics rescoring, and in vitro affinity assay

Human Snk is an evolutionarily conserved serine/threonine kinase essential for the maintenance of endocrine stability. The protein consists of a N-terminal catalytic domain and a C-terminal polo-box domain (PBD) that determines subcellular localization and substrate specificity. Here, an integrated strategy is described to explore the vast structural diversity space of Snk PBD-binding phosphopeptides at a molecular level using machine learning modeling, annealing optimization, dynamics simulation, and energetics rescoring, focusing on the recognition specificity and motif preference of the Snk PBD domain. We further performed a systematic rational design of potent phosphopeptide ligands for the domain based on the harvested knowledge, from which a few potent binders were also confirmed by fluorescence-based assays. A phosphopeptide PP17 was designed as a good binder with affinity improvement by 6.7-fold relative to the control PP0, while the other three designed phosphopeptides PP7, PP13, and PP15 exhibit a comparable potency with PP0. In addition, a basic recognition motif that divides potent Snk PBD-binding sequences into four residue blocks was defined, namely [Χ-5Χ-4]block1–[Ω-3Ω-2Ω-1]block2–[pS0/pT0]block3–[Ψ+1]block4, where the X represents any amino acid, Ω indicates polar amino acid, Ψ denotes hydrophobic amino acid, and pS0/pT0 is the anchor phosphoserine/phosphothreonine at reference residue position 0.

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来源期刊
European Biophysics Journal
European Biophysics Journal 生物-生物物理
CiteScore
4.30
自引率
0.00%
发文量
43
审稿时长
6-12 weeks
期刊介绍: The journal publishes papers in the field of biophysics, which is defined as the study of biological phenomena by using physical methods and concepts. Original papers, reviews and Biophysics letters are published. The primary goal of this journal is to advance the understanding of biological structure and function by application of the principles of physical science, and by presenting the work in a biophysical context. Papers employing a distinctively biophysical approach at all levels of biological organisation will be considered, as will both experimental and theoretical studies. The criteria for acceptance are scientific content, originality and relevance to biological systems of current interest and importance. Principal areas of interest include: - Structure and dynamics of biological macromolecules - Membrane biophysics and ion channels - Cell biophysics and organisation - Macromolecular assemblies - Biophysical methods and instrumentation - Advanced microscopics - System dynamics.
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