Rajeshwar T Rajitha, Krishnan Marimuthu
Center for Computational Natural Sciences and Bioinformatics, International Institute of Information Technology , Gachibowli, Hyderabad 500 032, India.
J Phys Chem B. 2017 May 25;121(20):5174-5186. doi: 10.1021/acs.jpcb.7b01402. Epub 2017 May 15.
A novel approach to accurately determine residue-specific noncovalent interaction strengths (ξ) of proteins from NMR-measured fast side chain motional parameters (O) is presented. By probing the environmental sensitivity of side chain conformational energy surfaces of individual residues of a diverse set of proteins, the microscopic connections between ξ, O, conformational entropy (S), conformational barriers, and rotamer stabilities established here are found to be universal among proteins. The results reveal that side chain flexibility and conformational entropy of each residue decrease with increasing ξ and that for each residue type there exists a critical range of ξ, determined primarily by the mean side chain conformational barriers, within which flexibility of any residue can be reversibly tuned from highly flexible (with O ∼ 0) to highly restricted (with O ∼ 1) by increasing ξ by ∼3 kcal/mol. Beyond this critical range of ξ, both side chain flexibility and conformational entropy are insensitive to ξ. The interrelationships between conformational dynamics, conformational entropy, and noncovalent interactions of protein side chains established here open up new avenues to probe perturbation-induced (for example, ligand-binding, temperature, pressure) changes in fast side chain dynamics and thermodynamics of proteins by comparing their conformational energy surfaces in the native and perturbed states.
本文提出了一种从核磁共振测量的快速侧链运动参数（O）准确确定蛋白质残基特异性非共价相互作用强度（ξ）的新方法。通过探测多种蛋白质中各个残基侧链构象能面的环境敏感性，发现这里建立的ξ、O、构象熵（S）、构象势垒和旋转异构体稳定性之间的微观联系在蛋白质中是普遍存在的。结果表明，每个残基的侧链灵活性和构象熵随着ξ的增加而降低，并且对于每种残基类型，都存在一个主要由平均侧链构象势垒决定的ξ临界范围，在这个范围内，通过将ξ增加约3千卡/摩尔，任何残基的灵活性都可以从高度灵活（O ∼ 0）可逆地调节到高度受限（O ∼ 1）。超过这个ξ临界范围，侧链灵活性和构象熵对ξ都不敏感。这里建立的蛋白质侧链构象动力学、构象熵和非共价相互作用之间的相互关系，通过比较蛋白质在天然状态和受扰状态下的构象能面，为探测扰动诱导（例如，配体结合、温度、压力）的快速侧链动力学和热力学变化开辟了新途径。
