Department of Molecular Biology, University of Wyoming, Laramie, Wyoming 82071, USA.
Protein Sci. 2012 Jun;21(6):769-85. doi: 10.1002/pro.2071. Epub 2012 Apr 23.
Abstract The interface of protein structural biology, protein biophysics, molecular evolution, and molecular population genetics forms the foundations for a mechanistic understanding of many aspects of protein biochemistry. Current efforts in interdisciplinary protein modeling are in their infancy and the state-of-the art of such models is described. Beyond the relationship between amino acid substitution and static protein structure, protein function, and corresponding organismal fitness, other considerations are also discussed. More complex mutational processes such as insertion and deletion and domain rearrangements and even circular permutations should be evaluated. The role of intrinsically disordered proteins is still controversial, but may be increasingly important to consider. Protein geometry and protein dynamics as a deviation from static considerations of protein structure are also important. Protein expression level is known to be a major determinant of evolutionary rate and several considerations including selection at the mRNA level and the role of interaction specificity are discussed. Lastly, the relationship between modeling and needed high-throughput experimental data as well as experimental examination of protein evolution using ancestral sequence resurrection and in vitro biochemistry are presented, towards an aim of ultimately generating better models for biological inference and prediction.
摘要 蛋白质结构生物学、蛋白质生物物理学、分子进化和分子群体遗传学的界面为理解蛋白质生物化学的许多方面提供了机制基础。目前，跨学科蛋白质建模的努力还处于起步阶段，本文描述了这些模型的现状。除了氨基酸替换与静态蛋白质结构、蛋白质功能和相应的生物体适应性之间的关系之外，还讨论了其他一些考虑因素。更复杂的突变过程，如插入和缺失、结构域重排甚至环状排列，也应该进行评估。尽管对内在无序蛋白质的作用仍存在争议，但考虑其作用可能会越来越重要。蛋白质几何形状和蛋白质动力学作为对蛋白质结构静态考虑的偏离，也是很重要的。蛋白质表达水平是进化率的主要决定因素，本文还讨论了包括在 mRNA 水平的选择以及相互作用特异性的作用等几个考虑因素。最后，本文提出了建模与所需高通量实验数据之间的关系，以及使用祖先序列复活和体外生物化学来研究蛋白质进化的实验检验，旨在最终生成更好的用于生物学推理和预测的模型。
