English Lance R, Tilton Erin C, Ricard Benjamin J, Whitten Steven T
Department of Chemistry and Biochemistry, Texas State University, San Marcos, Texas.
Proteins. 2017 Feb;85(2):296-311. doi: 10.1002/prot.25222. Epub 2017 Jan 5.
Proteins that lack tertiary stability under normal conditions, known as intrinsically disordered, exhibit a wide range of biological activities. Molecular descriptions for the biology of intrinsically disordered proteins (IDPs) consequently rely on disordered structural models, which in turn require experiments that assess the origins to structural features observed. For example, while hydrodynamic size is mostly insensitive to sequence composition in chemically denatured proteins, IDPs show strong sequence-specific effects in the hydrodynamic radius (R ) when measured under normal conditions. To investigate sequence-modulation of IDP R , disordered ensembles generated by a hard sphere collision model modified with a structure-based parameterization of the solution energetics were used to parse the contributions of net charge, main chain dihedral angle bias, and excluded volume on hydrodynamic size. Ensembles for polypeptides 10-35 residues in length were then used to establish power-law scaling relationships for comparison to experimental R from 26 IDPs. Results showed the expected outcomes of increased hydrodynamic size from increases in excluded volume and net charge, and compaction from chain-solvent interactions. Chain bias representing intrinsic preferences for α helix and polyproline II (PP ), however, modulated R with intricate dependence on the simulated propensities. PP propensities at levels expected in IDPs correlated with heightened R sensitivity to even weak α helix propensities, indicating bias for common (φ, ψ) are important determinants of hydrodynamic size. Moreover, data show that IDP R can be predicted from sequence with good accuracy from a small set of physicochemical properties, namely intrinsic conformational propensities and net charge. Proteins 2017; 85:296-311. © 2016 Wiley Periodicals, Inc.
在正常条件下缺乏三级稳定性的蛋白质，即所谓的内在无序蛋白质，表现出广泛的生物活性。因此，对内在无序蛋白质（IDP）生物学的分子描述依赖于无序结构模型，而这反过来又需要通过实验来评估所观察到的结构特征的起源。例如，虽然流体力学尺寸在化学变性蛋白质中对序列组成大多不敏感，但在正常条件下测量时，IDP在流体力学半径（R）上表现出强烈的序列特异性效应。为了研究IDP R的序列调节，使用了一种通过基于溶液能量学的结构参数化修改的硬球碰撞模型生成的无序集合，来解析净电荷、主链二面角偏差和排除体积对流体力学尺寸的贡献。然后使用长度为10 - 35个残基的多肽集合来建立幂律缩放关系，以便与26种IDP的实验R进行比较。结果显示了预期的结果，即排除体积和净电荷增加导致流体力学尺寸增大，以及链 - 溶剂相互作用导致压缩。然而，代表对α螺旋和多聚脯氨酸II（PP）内在偏好的链偏差，以对模拟倾向的复杂依赖性调节R。IDP中预期水平的PP倾向与R对甚至微弱的α螺旋倾向的更高敏感性相关，表明常见（φ，ψ）偏差是流体力学尺寸的重要决定因素。此外，数据表明，可以从一小部分物理化学性质，即内在构象倾向和净电荷，以良好的准确性从序列预测IDP R。蛋白质2017；85：296 - 311。©2016威利期刊公司。
