PMID- 31062393
OWN - NLM
STAT- MEDLINE
DCOM- 20200811
LR  - 20200811
IS  - 1096-987X (Electronic)
IS  - 0192-8651 (Linking)
VI  - 40
IP  - 22
DP  - 2019 Aug 15
TI  - Molecular dynamics simulation study on the inhibitory effects of 
      choline-O-sulfate on hIAPP protofibrilation.
PG  - 1957-1968
LID - 10.1002/jcc.25851 [doi]
AB  - Type 2 diabetes mellitus (T2Dm) is a neurodegenerative disease, which occurs due 
      to the self-association of human islet amyloid polypeptide (hIAPP), also known as 
      human amylin. It was reported experimentally that choline-O-sulfate (COS), a 
      small organic molecule having a tertiary amino group and sulfate group, can 
      prevent the aggregation of human amylin without providing the mechanism of the 
      action of COS in the inhibition process. In this work, we investigate the 
      influence of COS on the full-length hIAPP peptide by performing 500 ns classical 
      molecular dynamics simulations. From pure water simulation (without COS), we have 
      identified the residues 11-20 and 23-36 that mainly participate in the fibril 
      formation, but in the presence of 1.07 M COS these residues become totally free 
      of beta-sheet conformation. Our results also show that the sulfate oxygen of COS 
      directly interacts with the peptide backbone, which leads to the local disruption 
      of peptide-peptide interaction. Moreover, the presence of favorable peptide-COS 
      vdW interaction energy and high coordination number of COS molecules in the first 
      solvation shell of the peptide indicates the hydrophobic solvation of the peptide 
      residues by COS molecules, which also play a crucial role in the prevention of 
      beta-sheet formation. Finally, from the potential of mean force (PMFs) calculations, 
      we observe that the free energy between two peptides is more negative in the 
      absence of COS and with increasing concentration of COS, it becomes unfavorable 
      significantly indicating that the peptide dimer formation is most stable in pure 
      water, which becomes less favorable in the presence of COS. (c) 2019 Wiley 
      Periodicals, Inc.
CI  - (c) 2019 Wiley Periodicals, Inc.
FAU - Paul, Srijita
AU  - Paul S
AD  - Department of Chemistry, Indian Institute of Technology, Guwahati, Assam, India 
      781039.
FAU - Paul, Sandip
AU  - Paul S
AUID- ORCID: 0000-0002-9693-2915
AD  - Department of Chemistry, Indian Institute of Technology, Guwahati, Assam, India 
      781039.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20190506
PL  - United States
TA  - J Comput Chem
JT  - Journal of computational chemistry
JID - 9878362
RN  - 0 (Islet Amyloid Polypeptide)
RN  - N91BDP6H0X (Choline)
SB  - IM
MH  - Choline/*chemistry/*pharmacology
MH  - Diabetes Mellitus, Type 2/drug therapy/metabolism
MH  - Humans
MH  - Islet Amyloid Polypeptide/*antagonists & inhibitors/metabolism
MH  - *Molecular Dynamics Simulation
MH  - Molecular Structure
OTO - NOTNLM
OT  - aggregation
OT  - choline- O-sulfate
OT  - hIAPP
OT  - inhibition
OT  - molecular dynamics
EDAT- 2019/05/08 06:00
MHDA- 2020/08/12 06:00
CRDT- 2019/05/08 06:00
PHST- 2019/01/05 00:00 [received]
PHST- 2019/04/10 00:00 [revised]
PHST- 2019/04/16 00:00 [accepted]
PHST- 2019/05/08 06:00 [pubmed]
PHST- 2020/08/12 06:00 [medline]
PHST- 2019/05/08 06:00 [entrez]
AID - 10.1002/jcc.25851 [doi]
PST - ppublish
SO  - J Comput Chem. 2019 Aug 15;40(22):1957-1968. doi: 10.1002/jcc.25851. Epub 2019 
      May 6.