美国德州莱斯大学（Rice University）及Baylor医学院（Baylor college of medicine）的研究人员，利用数学算法与X-ray结晶学的信息结合，破解蛋白质结构中会移动的部分结构（moving parts），有助于对结构生物学分类的厘清，并对引起癌症或其它疾病蛋白质的活性区（active sites）有更多的了解。此研究发表于PNAS期刊。
Jianpeng Ma教授说：「这项技术对于较大、较复杂以及有弹性易弯由（flexible）的蛋白质结构区域的精细化（refinetment）有很大的帮助。利用数学算法及结晶学结果的信息对比，找到可能的蛋白质结构。」曾经是诺贝尔奖得主的哈佛大学教授William Lipscomb也表示：「这项研究对于蛋白质结构生物学领域的确是一项重大成就。」
蛋白质是由胺基酸一个一个串起来而形成的分子，目前的技术已能将这些胺基酸序列定义出来，但对于3D结构中较有弹性而会游动的部分，则仍然很难透过结晶学的技术直接解开，而这部分的蛋白质往往又是重要的功能区，例如：是酵素的催化中心或是讯息蛋白停靠的码头。因此，加速解开此区域的蛋白质结构，对于癌症或相关疾病的药物设计可说具有重要的意义。
Ma 教授说：「这些年来若没Billy Poon以及Xiaorui Chen这两位坚忍不拔的学生，日以继夜的配戴着特殊护目镜焚膏继晷的进行研究，不会有此革命性的研究出现。这个方法能改善许多蛋白质3D结构的译码，而事实上已证明此方法的适用性极高，并已解决许多膜蛋白（membrane proteins）结构的问题。」
（编译/陈瑞娟） (资料来源 : Bio.com)
原始出处：
Published online before print April 30, 2007, 10.1073/pnas.0701204104
PNAS | May 8, 2007 | vol. 104 | no. 19 | 7869-7874
Normal mode refinement of anisotropic thermal parameters for a supramolecular complex at 3.42-Å crystallographic resolution
Billy K. Poon, Xiaorui Chen, Mingyang Lu, Nand K. Vyas, Florante A. Quiocho, Qinghua Wang, and Jianpeng Ma,,,¶
Department of Bioengineering, Rice University, Houston, TX 77005; Graduate Program of Structural and Computational Biology and Molecular Biophysics and Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, One Baylor Plaza, BCM-125, Houston, TX 77030
Edited by William N. Lipscomb, Harvard University, Cambridge, MA, and approved March 27, 2007 (received for review February 8, 2007)
Abstract
Here we report a normal-mode-based protocol for modeling anisotropic thermal motions of proteins in x-ray crystallographic refinement. The foundation for this protocol is a recently developed elastic normal mode analysis that produces much more accurate eigenvectors without the tip effect. The effectiveness of the procedure is demonstrated on the refinement of a 3.42-Å structure of formiminotransferase cyclodeaminase, a 0.5-MDa homooctameric enzyme. Using an order of magnitude fewer adjustable thermal parameters than the conventional isotropic refinement, this protocol resulted in a decrease of the values of Rcryst and Rfree and improvements of the density map. Several poorly resolved regions in the original isotropically refined structure became clearer so that missing side chains were fitted easily and mistraced backbone was corrected. Moreover, the distribution of anisotropic thermal ellipsoids revealed functionally important structure flexibility. This normal-mode-based refinement is an effective way of describing anisotropic thermal motions in x-ray structures and is particularly attractive for the refinement of very large and flexible supramolecular complexes at moderate resolutions.
anisotropic temperature factor | conformational flexibility | elastic normal mode analysis | tip effect | x-ray crystallographic refinement
Fig. 1. Structure of FTCD. (a) The square doughnut structure of an FTCD octamer. Two subunits are shown in red and blue, respectively. (b) The subunit structure of ligand-free FTCD. Backbone trace color ramped from the N terminus to the C terminus. (c) Superposition of the FT domain of human ligand-free FTCD (red) with the structure of the same domain in isolation (cyan) with the product analog, folinic acid (CPK mode), bound in the groove. (d) Rainbow-colored isotropic B factor in the original model. The hotter the color, the larger the B factors. The high flexibility of the N-subdomain, the linker region, and the lower half of the CD domain is evident.
