title: Insights into the folding and unfolding processes of wild-type and mutated SH3 domain by molecular dynamics and replica exchange molecular dynamics simulations.
abstract: Src-homology regions 3 (SH3) domain is essential for the down-regulation of tyrosine kinase activity. Mutation A39V/N53P/V55L of SH3 is found to be relative to the urgent misfolding diseases. To gain insight, the human and gallus SH3 domains (PDB ID: 1NYG and 2LP5), including 58 amino acids in each protein, were selected for MD simulations (Amber11, ff99SB force field) and cluster analysis to investigate the influence of mutations on the spatial structure of the SH3 domain. It is found that the large conformational change of mutations mainly exists in three areas in the vicinity of protein core: RT loop, N-src loop, distal β-hairpin to 310 helix. The C-terminus of the mutated gallus SH3 is disordered after simulation, which represents the intermediate state of aggregation. The disappeared strong Hbond net in the mutated human and gallus systems will make these mutated proteins looser than the wild-type proteins. Additionally, by performing the REMD simulations on the gallus SH3 domain, the mutated domain is found to have an obvious effect on the unfolding process. These studies will be helpful for further aggregation mechanisms investigations on SH3 family.
authors.affiliation: State Key Laboratory of Theoretical and Computational Chemistry, Institute of Theoretical Chemistry, Jilin University, Changchun, Jilin, PR China.
authors.forename: Wen-Ting
authors.initials: WT
authors.lastname: Chu
authors.forename: Ji-Long
authors.initials: JL
authors.lastname: Zhang
authors.forename: Qing-Chuan
authors.initials: QC
authors.lastname: Zheng
authors.forename: Lin
authors.initials: L
authors.lastname: Chen
authors.forename: Hong-Xing
authors.initials: HX
authors.lastname: Zhang
mesh_terms: D000818:Animals; D030161:Avian Proteins / Q000737:chemistry / Q000235:genetics; D002645:Chickens; D006801:Humans; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D009154:Mutation; D017510:Protein Folding; D058767:Protein Unfolding; D011506:Proteins / Q000737:chemistry / Q000235:genetics; D051076:Proto-Oncogene Proteins c-fyn / Q000737:chemistry / Q000235:genetics; D013816:Thermodynamics; D018909:src Homology Domains / Q000235:genetics*
chemical_list: D030161:Avian Proteins; D011506:Proteins; D051076:Proto-Oncogene Proteins c-fyn