title: Protein dynamics and motions in relation to their functions: several case studies and the underlying mechanisms.
abstract: Proteins are dynamic entities in cellular solution with functions governed essentially by their dynamic personalities. We review several dynamics studies on serine protease proteinase K and HIV-1 gp120 envelope glycoprotein to demonstrate the importance of investigating the dynamic behaviors and molecular motions for a complete understanding of their structure-function relationships. Using computer simulations and essential dynamic (ED) analysis approaches, the dynamics data obtained revealed that: (i) proteinase K has highly flexible substrate-binding site, thus supporting the induced-fit or conformational selection mechanism of substrate binding; (ii) Ca(2+) removal from proteinase K increases the global conformational flexibility, decreases the local flexibility of substrate-binding region, and does not influence the thermal motion of catalytic triad, thus explaining the experimentally determined decreased thermal stability, reduced substrate affinity, and almost unchanged catalytic activity upon Ca(2+) removal; (iii) substrate binding affects the large concerted motions of proteinase K, and the resulting dynamic pocket can be connected to substrate binding, orientation, and product release; (iv) amino acid mutations 375 S/W and 423 I/P of HIV-1 gp120 have distinct effects on molecular motions of gp120, facilitating 375 S/W mutant to assume the CD4-bound conformation, while 423 I/P mutant to prefer for CD4-unliganded state. The mechanisms underlying protein dynamics and protein-ligand binding, including the concept of the free energy landscape (FEL) of the protein-solvent system, how the ruggedness and variability of FEL determine protein's dynamics, and how the three ligand-binding models, the lock-and-key, induced-fit, and conformational selection are rationalized based on the FEL theory are discussed in depth.
authors.affiliation: a Laboratory for Conservation and Utilization of Bio-Resources & Key Laboratory for Microbial Resources of the Ministry of Education , Yunnan University , Kunming , 650091 , P.R. China .
authors.forename: Li-Quan
authors.initials: LQ
authors.lastname: Yang
authors.forename: Peng
authors.initials: P
authors.lastname: Sang
authors.forename: Yan
authors.initials: Y
authors.lastname: Tao
authors.forename: Yun-Xin
authors.initials: YX
authors.lastname: Fu
authors.forename: Ke-Qin
authors.initials: KQ
authors.lastname: Zhang
authors.forename: Yue-Hui
authors.initials: YH
authors.lastname: Xie
authors.forename: Shu-Qun
authors.initials: SQ
authors.lastname: Liu
mesh_terms: D019286:Endopeptidase K / Q000737:chemistry* / Q000378:metabolism; D015699:HIV Envelope Protein gp120 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D056004:Molecular Dynamics Simulation; D009038:Motion; D009154:Mutation; D011485:Protein Binding; D011487:Protein Conformation; D013816:Thermodynamics
chemical_list: D015699:HIV Envelope Protein gp120; D019286:Endopeptidase K