扩展的含 RGD 肽的构象动力学。,Biomacromolecules

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扩展的含 RGD 肽的构象动力学。
Biomacromolecules ( IF 5.5 ) Pub Date : 2020-05-29 , DOI: 10.1021/acs.biomac.0c00506
William R Lindemann ₁ , Alexander J Mijalis ₂ , José L Alonso _{3,

4} , Peter P Borbat ₅ , Jack H Freed ₅ , M Amin Arnaout _{3,

4} , Bradley L Pentelute ₂ , Julia H Ortony ₁

Affiliation

RGD 是生物材料中用于细胞粘附的三肽的一个多产例子，但游离或表面结合的 RGD 三肽的效力比天然蛋白质中的 RGD 结构域低几个数量级。我们设计了一组不同长度的肽，由中心三个残基为RGD的纤连蛋白片段组成，以便在不改变结合位点化学环境的情况下改变其构象行为。利用这些肽，我们测量活性位点的构象动力学和瞬时结构。我们的研究揭示了侧翼残基如何影响构象行为和整合素结合。我们发现结合位点的紊乱对于 RGD 肽的效力很重要，并且 RGD 位点附近的瞬时氢键会影响肽的能量景观粗糙度和肽结合。这种现象与长距离折叠相互作用无关，有助于解释为什么短结合序列（包括 RGD 本身）不能完全复制细胞外基质蛋白的整合素靶向特性。我们的研究强调，肽结合是一个整体事件，在设计功能性生物材料的肽表位时应考虑比直接参与结合的片段更大的片段。

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Conformational Dynamics in Extended RGD-Containing Peptides.

RGD is a prolific example of a tripeptide used in biomaterials for cell adhesion, but the potency of free or surface-bound RGD tripeptide is orders-of-magnitude less than the RGD domain within natural proteins. We designed a set of peptides with varying lengths, composed of fragments of fibronectin protein whose central three residues are RGD, in order to vary their conformational behavior without changing the binding site’s chemical environment. With these peptides, we measure the conformational dynamics and transient structure of the active site. Our studies reveal how flanking residues affect conformational behavior and integrin binding. We find that disorder of the binding site is important to the potency of RGD peptides and that transient hydrogen bonding near the RGD site affects both the energy landscape roughness of the peptides and peptide binding. This phenomenon is independent of longer-range folding interactions and helps explain why short binding sequences, including RGD itself, do not fully replicate the integrin-targeting properties of extracellular matrix proteins. Our studies reinforce that peptide binding is a holistic event and fragments larger than those directly involved in binding should be considered in the design of peptide epitopes for functional biomaterials.

更新日期：2020-07-13

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