Mapping Allostery through Computational Glycine Scanning and Correlation Analysis of Residue鈥揜esidue Contacts

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• 作者：Quentin R. Johnson ; Richard J. Lindsay ; Ricky B. Nellas ; Elias J. Fernandez ; Tongye Shen
• 刊名：Biochemistry
• 出版年：2015
• 出版时间：February 24, 2015
• 年：2015
• 卷：54
• 期：7
• 页码：1534-1541
• 全文大小：454K
• ISSN：1520-4995

文摘

Understanding allosteric mechanisms is essential for the physical control of molecular switches and downstream cellular responses. However, it is difficult to decode essential allosteric motions in a high-throughput scheme. A general two-pronged approach to performing automatic data reduction of simulation trajectories is presented here. The first step involves coarse-graining and identifying the most dynamic residue鈥搑esidue contacts. The second step is performing principal component analysis of these contacts and extracting the large-scale collective motions expressed via these residue鈥搑esidue contacts. We demonstrated the method using a protein complex of nuclear receptors. Using atomistic modeling and simulation, we examined the protein complex and a set of 18 glycine point mutations of residues that constitute the binding pocket of the ligand effector. The important motions that are responsible for the allostery are reported. In contrast to conventional induced-fit and lock-and-key binding mechanisms, a novel 鈥渇rustrated-fit鈥?binding mechanism of RXR for allosteric control was revealed.