A computational protocol for the integration of the monotopic protein prostaglandin H2 synthase into a phospholipid bilayer.

Biophysical Journal
Philip W Fowler, Peter V Coveney

Abstract

Prostaglandin H2 synthase (PGHS) synthesizes PGH2, a prostaglandin precursor, from arachidonic acid and was the first monotopic enzyme to have its structure experimentally determined. Both isozymes of PGHS are inhibited by nonsteroidal antiinflammatory drugs, an important class of drugs that are the primary means of relieving pain and inflammation. Selectively inhibiting the second isozyme, PGHS-2, minimizes the gastrointestinal side-effects. This had been achieved by the new PGHS-2 selective NSAIDs (i.e., COX-2 inhibitors) but it has been recently suggested that they suffer from additional side-effects. The design of these drugs only made use of static structures from x-ray crystallographic experiments. Investigating the dynamics of both PGHS-1 and PGHS-2 using classical molecular dynamics is expected to generate new insight into the differences in behavior between the isozymes, and therefore may allow improved PGHS-2 selective inhibitors to be designed. We describe a molecular dynamics protocol that integrates PGHS monomers into phospholipid bilayers, thereby producing in silico atomistic models of the PGHS system. Our protocol exploits the vacuum created beneath the protein when several lipids are removed from the top leafle...Continue Reading

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Citations

Mar 22, 2013·Cell Biochemistry and Biophysics·Dai-Chi LiuChih-Yung Tang
Sep 18, 2007·Langmuir : the ACS Journal of Surfaces and Colloids·Alik S WidgeMaria Kurnikova
Jan 19, 2008·Prostaglandins & Other Lipid Mediators·J Rand DoyenRichard J Kulmacz
Jun 2, 2010·Biophysical Journal·Shuangyang LiWenchuan Wang
Apr 16, 2013·Journal of Biomolecular Structure & Dynamics·Madza Yasodara Farias VirgensMaria Luiza Saraiva-Pereira
Oct 24, 2008·Journal of Computational Chemistry·Shunzhou Wan, Peter V Coveney
May 3, 2019·PLoS Computational Biology·Yihao ZhangGeorge Lykotrafitis
Nov 2, 2019·European Journal of Pharmacology·Jolanta HybiakElżbieta Urasińska
May 13, 2011·The Journal of Physical Chemistry. B·Mark J ArcarioEmad Tajkhorshid
Jun 20, 2015·Journal of Chemical Theory and Computation·Elizabeth JefferysPhilip W Fowler
Feb 22, 2007·Biochemistry·Philip W FowlerMark S P Sansom

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