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@ARTICLE{Ahmad:902474,
      author       = {Ahmad, Sabahuddin and Strunk, Christoph Heinrich and
                      Schott, Stephan and Jaeger, Karl-Erich and Kovacic, Filip
                      and Gohlke, Holger},
      title        = {{S}ubstrate {A}ccess {M}echanism in a {N}ovel
                      {M}embrane-{B}ound {P}hospholipase {A} of {P}seudomonas
                      aeruginosa {C}oncordant with {S}pecificity and
                      {R}egioselectivity},
      journal      = {Journal of chemical information and modeling},
      volume       = {61},
      number       = {11},
      issn         = {0095-2338},
      address      = {Washington, DC},
      publisher    = {American Chemical Society},
      reportid     = {FZJ-2021-04293},
      pages        = {5626–5643},
      year         = {2021},
      abstract     = {PlaF is a cytoplasmic membrane-bound phospholipase A1 from
                      Pseudomonas aeruginosa that alters the membrane
                      glycerophospholipid (GPL) composition and fosters the
                      virulence of this human pathogen. PlaF activity is regulated
                      by a dimer-to-monomer transition followed by tilting of the
                      monomer in the membrane. However, how substrates reach the
                      active site and how the characteristics of the active site
                      tunnels determine the activity, specificity, and
                      regioselectivity of PlaF for natural GPL substrates have
                      remained elusive. Here, we combined unbiased and biased
                      all-atom molecular dynamics (MD) simulations and
                      configurational free-energy computations to identify access
                      pathways of GPL substrates to the catalytic center of PlaF.
                      Our results map out a distinct tunnel through which
                      substrates access the catalytic center. PlaF variants with
                      bulky tryptophan residues in this tunnel revealed decreased
                      catalysis rates due to tunnel blockage. The MD simulations
                      suggest that GPLs preferably enter the active site with the
                      sn-1 acyl chain first, which agrees with the experimentally
                      demonstrated PLA1 activity of PlaF. We propose that the acyl
                      chain-length specificity of PlaF is determined by the
                      structural features of the access tunnel, which results in
                      favorable free energy of binding of medium-chain GPLs. The
                      suggested egress route conveys fatty acid (FA) products to
                      the dimerization interface and, thus, contributes to
                      understanding the product feedback regulation of PlaF by
                      FA-triggered dimerization. These findings open up
                      opportunities for developing potential PlaF inhibitors,
                      which may act as antibiotics against P. aeruginosa.},
      cin          = {IBG-4 / JSC / NIC / IBI-7 / IMET},
      ddc          = {540},
      cid          = {I:(DE-Juel1)IBG-4-20200403 / I:(DE-Juel1)JSC-20090406 /
                      I:(DE-Juel1)NIC-20090406 / I:(DE-Juel1)IBI-7-20200312 /
                      I:(DE-Juel1)IMET-20090612},
      pnm          = {2171 - Biological and environmental resources for
                      sustainable use (POF4-217) / 5111 - Domain-Specific
                      Simulation $\&$ Data Life Cycle Labs (SDLs) and Research
                      Groups (POF4-511) / Forschergruppe Gohlke $(hkf7_20200501)$
                      / DFG project 267205415 - SFB 1208: Identität und Dynamik
                      von Membransystemen - von Molekülen bis zu zellulären
                      Funktionen (267205415)},
      pid          = {G:(DE-HGF)POF4-2171 / G:(DE-HGF)POF4-5111 /
                      $G:(DE-Juel1)hkf7_20200501$ / G:(GEPRIS)267205415},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:34748335},
      UT           = {WOS:000757001900030},
      doi          = {10.1021/acs.jcim.1c00973},
      url          = {https://juser.fz-juelich.de/record/902474},
}