Al Mughram Mohammed H, Catalano Claudio, Herrington Noah B, Safo Martin K, Kellogg Glen E
Department of Medicinal Chemistry and the Institute for Structural Biology, Drug Discovery and Development, Virginia Commonwealth University, Richmond, VA, United States.
Center for the Study of Biological Complexity, Virginia Commonwealth University, Richmond, VA, United States.
Front Mol Biosci. 2023 Mar 28;10:1116868. doi: 10.3389/fmolb.2023.1116868. eCollection 2023.
The aliphatic hydrophobic amino acid residues-alanine, isoleucine, leucine, proline and valine-are among the most common found in proteins. Their structural role in proteins is seemingly obvious: engage in hydrophobic interactions to stabilize secondary, and to a lesser extent, tertiary and quaternary structure. However, favorable hydrophobic interactions involving the sidechains of these residue types are generally less significant than the unfavorable set arising from interactions with polar atoms. Importantly, the constellation of interactions between residue sidechains and their environments can be recorded as three-dimensional maps that, in turn, can be clustered. The clustered average map sets compose a library of interaction profiles encoding interaction strengths, interaction types and the optimal 3D position for the interacting partners. This library is backbone angle-dependent and suggests solvent and lipid accessibility for each unique interaction profile. In this work, in addition to analysis of soluble proteins, a large set of membrane proteins that contained optimized artificial lipids were evaluated by parsing the structures into three distinct components: soluble extramembrane domain, lipid facing transmembrane domain, core transmembrane domain. The aliphatic residues were extracted from each of these sets and passed through our calculation protocol. Notable observations include: the roles of aliphatic residues in soluble proteins and in the membrane protein's soluble domains are nearly identical, although the latter are slightly more solvent accessible; by comparing maps calculated with sidechain-lipid interactions to maps ignoring those interactions, the potential extent of residue-lipid and residue-interactions can be assessed and likely exploited in structure prediction and modeling; amongst these residue types, the levels of lipid engagement show isoleucine as the most engaged, while the other residues are largely interacting with neighboring helical residues.
脂肪族疏水氨基酸残基（丙氨酸、异亮氨酸、亮氨酸、脯氨酸和缬氨酸）是蛋白质中最常见的残基类型。它们在蛋白质中的结构作用似乎很明显：参与疏水相互作用以稳定二级结构，在较小程度上也稳定三级和四级结构。然而，涉及这些残基类型侧链的有利疏水相互作用通常不如与极性原子相互作用产生的不利相互作用显著。重要的是，残基侧链与其环境之间的相互作用组合可以记录为三维图谱，进而可以进行聚类。聚类后的平均图谱集构成了一个相互作用谱库，编码相互作用强度、相互作用类型以及相互作用伙伴的最佳三维位置。这个库依赖于主链角度，并为每个独特的相互作用谱提示溶剂和脂质可及性。在这项工作中，除了分析可溶性蛋白质外，还通过将大量含有优化人工脂质的膜蛋白结构解析为三个不同部分（可溶性胞外结构域、面向脂质的跨膜结构域、核心跨膜结构域）来进行评估。从这些结构中提取脂肪族残基，并使其通过我们的计算方案。值得注意的观察结果包括：脂肪族残基在可溶性蛋白质和膜蛋白可溶性结构域中的作用几乎相同，尽管后者的溶剂可及性稍高一些；通过将计算得到的侧链 - 脂质相互作用图谱与忽略这些相互作用的图谱进行比较，可以评估残基 - 脂质和残基 - 残基相互作用的潜在程度，并可能在结构预测和建模中加以利用；在这些残基类型中，脂质参与程度显示异亮氨酸最高，而其他残基主要与相邻的螺旋残基相互作用。
