Foldamer Tertiary Structure through Sequence-Guided Protein Backbone Alteration.
Foldamer Tertiary Structure through Sequence-Guided Protein Backbone Alteration.
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DOI：
10.1021/acs.accounts.8b00048
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发表时间：
2018-05-15
影响因子：
18.3
通讯作者：
Horne WS
中科院分区：
文献类型：
--
作者：
George KL;Horne WS
在具有共价结构的人工主链（“折叠体”）的合成低聚物中重建蛋白质折叠的复杂结构层次的前景长期以来一直令化学家着迷。折叠分子通过生物稳定支架提供复杂的功能，并在生物医学到材料科学等领域得到广泛应用。大多数先例都集中在孤立的二级结构或其组件上。在考虑复杂的类蛋白质三级折叠模式的目标时，一个关键障碍变得明显。如何设计具有共价连接性和一系列侧链官能团的主链，以支持多个人工二级结构的确定的分子内堆积？两项发展是克服这一挑战的关键。首先是认识到将 α-氨基酸残基与主链连接性不同的单体混合以创建“异质主链”折叠体的能力。其次，我们发现用人工主链变体替换生物序列中的一些天然 α 残基可以产生保留天然序列的折叠和功能的模拟物，并且在某些情况下获得有利的特征。总而言之，这些先例导致了将蛋白质视为具有两个正交序列的化学实体的观点：侧链官能团的序列和显示这些官能团的主链单元的单独序列。在本报告中，我们描述了我们实验室在过去约 10 年中利用上述蛋白质序列二元性概念的工作，以开发构建采用复杂的类蛋白质三级折叠的异质骨架折叠体的设计原则。该方法的基础是协同利用各种人工构建模块（例如，D-α-残基、Cα-Me-α-残基、N-Me-α-残基、β-残基、γ-残基、δ-残基、聚合物片段），替换给定原型序列中的一小部分α-残基。我们根据局部二级结构和关键侧链官能团保留的考虑，概述了选择取代的设计原则的最新技术。我们研究了骨架修饰蛋白的高分辨率结构，以说明不同的人工部分如何适应三级折叠环境。我们详细介绍了阐明主链改变如何影响折叠热力学的努力，并描述了这些数据如何为改进设计规则的开发提供信息。总的来说，我们的实验室和其他跨越多个蛋白质系统的越来越多的结果表明，序列编码的三级折叠可以体现的主链化学结构具有很大的可塑性。此外，这些努力表明序列引导的主链改变是一种广泛适用的策略，用于生成具有复杂三级折叠模式的折叠体。最后，我们从未解答的问题、技术需求和新研究领域的机会方面提供了对该领域近期未来的一些看法。
The prospect of recreating the complex structural hierarchy of protein folding in synthetic oligomers with backbones that are artificial in covalent structure (“foldamers”) has long fascinated chemists. Foldamers offer complex functions from biostable scaffolds and have found widespread applications in fields from biomedical to materials science. Most precedent has focused on isolated secondary structures or their assemblies. In considering the goal of complex protein-like tertiary folding patterns, a key barrier became apparent. How does one design a backbone with covalent connectivity and a sequence of side-chain functional groups that will support defined intramolecular packing of multiple artificial secondary structures? Two developments were key to overcoming this challenge. First was the recognition of the power of blending α-amino acid residues with monomers differing in backbone connectivity to create “heterogeneous-backbone” foldamers. Second was the finding that replacing some of the natural α-residues in a biological sequence with artificial-backbone variants can result in a mimic that retains both the fold and function of the native sequence and, in some cases, gains advantageous characteristics. Taken together, these precedents lead to a view of a protein as chemical entity having two orthogonal sequences: a sequence of side-chain functional groups and a separate sequence of backbone units displaying those functional groups. In this Account, we describe our lab’s work over the last ~10 years to leverage the above concept of protein sequence duality in order to develop design principles for constructing heterogeneous-backbone foldamers that adopt complex protein-like tertiary folds. Fundamental to the approach is the utilization of a variety of artificial building blocks (e.g., D-α-residues, Cα-Me-α-residues, N-Me- α-residues, β-residues, γ-residues, δ-residues, polymer segments) in concert, replacing a fraction of α-residues in a given prototype sequence. We provide an overview of the state-of-the-art in terms of design principles for choosing substitutions based on consideration of local secondary structure and retention of key side-chain functional groups. We survey high-resolution structures of backbone-modified proteins to illustrate how diverse artificial moieties are accommodated in tertiary fold contexts. We detail efforts to elucidate how backbone alteration impacts folding thermodynamics and describe how such data informs the development of improved design rules. Collectively, a growing body of results by our lab and others spanning multiple protein systems suggests there is a great deal of plasticity with respect to the backbone chemical structures upon which sequence-encoded tertiary folds can manifest. Moreover, these efforts suggest sequence-guided backbone alteration as a broadly applicable strategy for generating foldamers with complex tertiary folding patterns. We conclude by offering some perspective regarding the near future of this field, in terms of unanswered questions, technological needs, and opportunities for new areas of inquiry.
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