Department of Computational and Systems Biology, School of Medicine, University of Pittsburgh, 800 Murdoch Building, 3420 Forbes Avenue, Pittsburgh, PA 15213 USA.
Research Center for Computer-Aided Drug Discovery at Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China.
Curr Opin Struct Biol. 2021 Apr;67:25-32. doi: 10.1016/j.sbi.2020.08.009. Epub 2020 Oct 11.
Many proteins select from a small repertoire of 3-dimensional folds retained over evolutional timescales and recruited for different functions, with changes in local structure and sequence to enable specificity. Recent studies have revealed the evolutionary constraints on protein dynamics to achieve function. The significance of protein dynamics in simultaneously satisfying conformational flexibility/malleability and stability/precision requirements becomes clear upon dissecting the spectrum of equilibrium motions accessible to fold families. Accessibility to highly conserved global modes of motions shared by family members, to low-to-intermediate-frequency modes that distinguish subfamilies and confer specificity, and to conserved high-frequency modes ensuring chemical precision and core stability underlies functional specialization while exploiting highly versatile folds. These design principles are illustrated for the family of PDZ domains.
许多蛋白质从进化时间尺度上保留的小 3 维折叠库中选择，并被招募用于不同的功能，其局部结构和序列发生变化以实现特异性。最近的研究揭示了蛋白质动力学实现功能的进化限制。通过剖析折叠家族可获得的平衡运动谱，蛋白质动力学在同时满足构象灵活性/可塑性和稳定性/精度要求方面的重要性变得清晰起来。可及性包括家族成员共享的高度保守的全局运动模式、区分亚家族并赋予特异性的低至高频率模式，以及确保化学精度和核心稳定性的保守高频模式，这些都是功能专业化的基础，同时利用了高度通用的折叠。这些设计原则在 PDZ 结构域家族中得到了说明。
