title: Mapping central α-helix linker mediated conformational transition pathway of calmodulin via simple computational approach.
abstract: The effects of intrinsic structural flexibility of calmodulin protein on the mechanism of its allosteric conformational transition are investigated in this article. Using a novel in silico approach, the conformational transition pathways of intact calmodulin as well as the isolated N- and C- terminal domains are identified and energetically characterized. It is observed that the central α-helix linker amplifies the structural flexibility of intact Ca(2+)-free calmodulin, which might facilitate the transition of the two domains. As a result, the global conformational transition of Ca(2+)-free calmodulin is initiated by the barrierless transition of two domains and proceeds through the barrier associated unwinding and bending of the central α-helix linker. The binding of Ca(2+) cations to calmodulin further increases the structural flexibility of the C-terminal domain and results in a downhill transition pathway of which all regions transit in a concerted manner. On the other hand, the separation of the N- and C-terminal domains from calmodulin protein loses the mediating function of central α-helix linker, leading to more difficult conformational transitions of both domains. The present study provides novel insights into the correlation of the integrity of protein, the structural flexibility, and the mechanism of conformational transition of proteinlike calmodulin.
authors.affiliation: Drug Discovery and Design Center, Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , 555 Zuchongzhi Road, Shanghai 201203, China.
authors.forename: Jinan
authors.initials: J
authors.lastname: Wang
authors.forename: Shaoliang
authors.initials: S
authors.lastname: Peng
authors.forename: Benjamin P
authors.initials: BP
authors.lastname: Cossins
authors.forename: Xiangke
authors.initials: X
authors.lastname: Liao
authors.forename: Kaixian
authors.initials: K
authors.lastname: Chen
authors.forename: Qiang
authors.initials: Q
authors.lastname: Shao
authors.forename: Xiaoqian
authors.initials: X
authors.lastname: Zhu
authors.forename: Jiye
authors.initials: J
authors.lastname: Shi
authors.forename: Weiliang
authors.initials: W
authors.lastname: Zhu
mesh_terms: D000494:Allosteric Regulation; D002118:Calcium / Q000378:metabolism; D002147:Calmodulin / Q000737:chemistry* / Q000378:metabolism*; D003198:Computer Simulation; D056004:Molecular Dynamics Simulation; D011487:Protein Conformation
chemical_list: D002147:Calmodulin; D002118:Calcium