Molecular Dynamics Simulation On The Correlation Between Structure And Function Of The C-terminal And Zinc Finger Of The Yeast Ydj1p

Many cellular events such as genetic mutation or genetic diseases actually are associated with protein misfolding.Since molecular chaperones can facilitate folding,degradation,or preventing aggregation in the cell,thus,it is important to study the structure,function,and mechanisms of molecular chaperones for the explanation of some diseases.AS one of the molecular chaperones,Hsp40 regulates protein folding through C-terminal fragment dimerization.In this paper,steered molecular dynamics(SMD)simulations were performed to investigate the dissociation process between helix ?3 and domain? of Ydj1p(a yeast Hsp40 homologue)C-terminal dimerization,and to investigate the important residues and intermolecular interactions that influence Ydj1 p dimer stability.Our data indicate that residues L274,I278,F335,P336,F340,L346,L349,L352,L353 in ?2,?3 and the loop before ?3 forming a hydrophobic box,which stabilized the two helices.F335 of the loop before ?3 formed hydrophobic interactions with the side-chains of domain? residues V302,I278,I303 and P305.P336 also formed hydrophobic interactions with the side-chain of V302 in domain? to stabilize Ydj1 p dimer structure.In addition,The yeast Hsp40 Ydj1 p contains a conserved zinc finger-like region(ZFLR),which has two zinc-binding domains(ZBD),that helps regulate and specify Hsp70 function.Biochemical experiments studied Ydj1 p is required for Hsp70 to capture non-native proteins from Ydj1 p.Purified Ydj1 p ZBDI and ZBDII mutants could bind non-native polypeptides but could not deliver luciferase to Hsp70 and were defective at luciferase refolding.In this paper,molecular dynamics(MD)simulations were performed to investigate the reason for Ydj1 p ZFLR mutants function defective.Through comparison with different times conformational change and substrate binding energy.The results show(1),The number of hydrogen bonds and hydrophobic between the C143 S,C162S mutants and substrates is less than WT,and the total energy slightly less than the wild type too,The number of hydrophobic and hydrogen bonds between C201 S,C185S mutants and the substrate is similar to the wild-type.and the total energy is similar to the wild-type too.Thus,mutation of ZBDI or ZBDII does not alter the ability of Ydj1 p to bind substrates.(2)WT,C143 S,C162S and Hsp70 can interaction,due to C143 S and C162 S mutants conformational changes reducing substrate transfer efficiency to Hsp70.The J-domain-related Hsp40 and Hsp70 interaction mechanism has been in-depth study,Hsp40 other sites interaction with Hsp70 has also been reported,but the mechanism is not clear yet,in this paper,molecular docking and molecular dynamics simulations were performed to investigate interaction between Hsp70 and Hsp40 Ydj1 p.and to investigate the important residues and intermolecular interactions between Hsp70 C-terminal and Hsp40 Ydj1 p,also predicted the Ydj1 p interaction with Hsp70 key amino acid residues.