Conformational Changes of Glutamine 5′-Phosphoribosylpyrophosphate Amidotransferase for Two Substrates Analogue Binding: Insight from Conventional Molecular Dynamics and Accelerated Molecular Dynamics Simulations

Frontiers in Chemistry

卷:9

Hao Chang¹  Congcong Li²  Weiwei Han²  Fangning Zhang²  Tianci Huang²  Wannan Li²  Jiawei Yuan²  Siao Chen² 

[1] Jilin Province TeyiFood Biotechnology Company Limited, Changchun, China;

[2] Key Laboratory for Molecular Enzymology and Engineering of Ministry of Education, Engineering Laboratory for AIDS Vaccine, School of Life Science, Jilin University, Changchun, China;

关键词: 5′-phosphoribosylpyrophosphate amidotransferase;    substrates analogue;    molecular dynamics simulations;    accelerated molecular dynamics simulations;    conformational changes;   

DOI  :  10.3389/fchem.2021.640994

来源: DOAJ

【 摘 要 】

Glutamine 5′-phosphoribosylpyrophosphate amidotransferase (GPATase) catalyzes the synthesis of phosphoribosylamine, pyrophosphate, and glutamate from phosphoribosylpyrophosphate, as well as glutamine at two sites (i.e., glutaminase and phosphoribosylpyrophosphate sites), through a 20 Å NH3 channel. In this study, conventional molecular dynamics (cMD) simulations and enhanced sampling accelerated molecular dynamics (aMD) simulations were integrated to characterize the mechanism for coordination catalysis at two separate active sites in the enzyme. Results of cMD simulations illustrated the mechanism by which two substrate analogues, namely, DON and cPRPP, affect the structural stability of GPATase from the perspective of dynamic behavior. aMD simulations obtained several key findings. First, a comparison of protein conformational changes in the complexes of GPATase–DON and GPATase–DON–cPRPP showed that binding cPRPP to the PRTase flexible loop (K326 to L350) substantially effected the formation of the R73-DON salt bridge. Moreover, only the PRTase flexible loop in the GPATase–DON–cPRPP complex could remain closed and had sufficient space for cPRPP binding, indicating that binding of DON to the glutamine loop had an impact on the PRTase flexible loop. Finally, both DON and cPRPP tightly bonded to the two domains, thereby inducing the glutamine loop and the PRTase flexible loop to move close to each other. This movement facilitated the transfer of NH3 via the NH3 channel. These theoretical results are useful to the ongoing research on efficient inhibitors related to GPATase.

【 授权许可】

Unknown