Atomistic view of the conformational activation of Src kinase using the string method with swarms-of-trajectories.
The inactive-to-active conformational transition of the catalytic domain of human c-Src tyrosine kinase is characterized using the string method with swarms-of-trajectories with all-atom explicit solvent molecular dynamics simulations. The activation process occurs in two main steps in which the activation loop (A-loop) opens first, followed by the rotation of the alphaC helix. The computed potential of mean force energy along the activation pathway displays a local minimum, which allows the identification of an intermediate state. These results show that the string method with swarms-of-trajectories is an effective technique to characterize complex and slow conformational transitions in large biomolecular systems.
Gan
Wenxun
W
Yang
Sichun
S
Roux
Benoît
B
D001665:Binding Sites; D000081247:CSK Tyrosine-Protein Kinase; D002384:Catalysis; D003198:Computer Simulation; D004789:Enzyme Activation; D008956:Models, Chemical; D008958:Models, Molecular; D011485:Protein Binding; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D011505:Protein-Tyrosine Kinases / Q000737:chemistry* / Q000648:ultrastructure*; D011518:Proto-Oncogene Proteins / Q000737:chemistry* / Q000648:ultrastructure*; D019061:src-Family Kinases
D011518:Proto-Oncogene Proteins; D011505:Protein-Tyrosine Kinases; D000081247:CSK Tyrosine-Protein Kinase; D019061:src-Family Kinases; C000631346:CSK protein, human
Structure. 2005 Jun;13(6):861-71
15939018
J Phys Chem B. 2005 Apr 14;109(14):6688-93
16851751
Proteins. 2007 Jun 1;67(4):1096-112
17380483
J Phys Chem B. 2008 Mar 20;112(11):3432-40
18290641
Mol Cell. 1999 May;3(5):629-38
10360179
J Am Chem Soc. 2009 Jan 14;131(1):244-50
19067513
Structure. 2005 Nov;13(11):1715-23
16271895
Proc Natl Acad Sci U S A. 2009 Jan 6;106(1):139-44
19109437
Protein Sci. 2006 May;15(5):1051-62
16597828
Proc Natl Acad Sci U S A. 2007 Sep 11;104(37):14559-64
17726097
Oncogene. 2004 Oct 18;23(48):7906-9
15489908
PLoS Comput Biol. 2008 Mar 28;4(3):e1000047
18369437
Proteins. 2009 Feb 1;74(2):378-89
18623061
J Chem Phys. 2006 Jul 14;125(2):24106
16848576
Cell. 2001 Apr 6;105(1):115-26
11301007
Oncogene. 1993 Aug;8(8):2025-31
8336932
Proc Natl Acad Sci U S A. 2009 Mar 10;106(10):3776-81
19225111
Protein Sci. 2008 Nov;17(11):1871-80
18687871