期刊
JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS
卷 29, 期 5, 页码 905-920出版社
TAYLOR & FRANCIS INC
DOI: 10.1080/073911012010525026
关键词
Molecular dynamics simulations; Serine protease inhibitors; Glycosylation; Fucosylation; Disulfide bonds and PMP-C
资金
- Department of Biotechnology (DBT), Government of India
- CSIR, India
- Department of Science and Technology, Govt. of India
Fucosylation of Thr9 in pars intercerebralis major peptide-C (PMP-C) enhances its structural stability and functional ability as a serine protease inhibitor. In order to understand the role of disulfide bonds and glycosylation on the structure and function of PMP-C, we have carried out multiple explicit solvent molecular dynamics (MD) simulations on fucosylated and non-fucosylated forms of PMP-C, both in the presence and absence of the disulfide bonds. Our simulations revealed that there were no significant structural changes in the native disulfide bonded forms of PMP-C due to fucosylation. On the other hand, the non-fucosylated form of PMP-C without disulfide bonds showed larger deviations from the starting structure than the fucosylated form. However, the structural deviations were restricted to the terminal regions while core p-sheet retained its hydrogen bonded structure even in absence of disulfide bonds as well as fucosylation. Interestingly, fucosylation of disulfide bonded native PMP-C led to a decreased thermal flexibility in the residue stretch 29-32 which is known to interact with the active site of the target proteases. Our analysis revealed that disulfide bonds covalently connect the residue stretch 29-32 to the central beta-sheet of PMP-C and using a novel network of side chain interactions and disulfide bonds fucosylation at Thr9 is altering the flexibility of the stretch 29-32 located at a distal site. Thus, our simulations explain for the first time, how presence of disulfide bonds between conserved cysteines and fucosylation enhance the function of PMP-C as a protease inhibitor.
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