KLK14 interactions with HAI-1 and HAI-2 serine protease inhibitors: A molecular dynamics and relative free-energy calculations study

Cell Biol Int. 2017 Nov;41(11):1246-1264. doi: 10.1002/cbin.10839. Epub 2017 Sep 17.

Abstract

Kallikrein 14 (KLK14) is a serine protease linked to several pathologies including prostate cancer and positively correlates with Gleason score. Though KLK14 functioning in cancer is poorly understood, it has been implicated in HGF/Met signaling, given that KLK14 proteolytically inhibits HGF activator-inhibitor 1 (HAI-1), which strongly inhibits pro-HGF activators, thereby contributing to tumor progression. In this work, KLK14 binding to either hepatocyte growth factor activator inhibitor type-1 (HAI-1) or type-2 (HAI-2) was essayed using homology modeling, molecular dynamic simulations and free-energy calculations through MM/PBSA and MM/GBSA. KLK14 was successfully modeled. Calculated free energies suggested higher binding affinity for the KLK14/HAI-1 interaction than for KLK14/HAI-2. This difference in binding affinity is largely explained by the higher stability of the hydrogen-bond networks in KLK14/HAI-1 along the simulation trajectory. A key arginine residue in both HAI-1 and HAI-2 is responsible for their interaction with the S1 pocket in KLK14. Additionally, MM/GBSA free-energy decomposition postulates that KLK14 Asp174 and Trp196 are hotspots for binding HAI-1 and HAI-2.

Keywords: HAI-1; HAI-2; HGF/Met signaling; KLK14; molecular dynamics simulations; prostate cancer.

MeSH terms

  • Amino Acid Sequence
  • Computational Biology / methods
  • Humans
  • Kallikreins / chemistry
  • Kallikreins / metabolism*
  • Male
  • Membrane Glycoproteins / antagonists & inhibitors
  • Membrane Glycoproteins / chemistry
  • Membrane Glycoproteins / metabolism*
  • Models, Molecular
  • Molecular Dynamics Simulation
  • Prostatic Neoplasms / metabolism
  • Protein Binding
  • Proteinase Inhibitory Proteins, Secretory / antagonists & inhibitors
  • Proteinase Inhibitory Proteins, Secretory / chemistry
  • Proteinase Inhibitory Proteins, Secretory / metabolism*
  • Proteolysis
  • RNA, Messenger / metabolism

Substances

  • Membrane Glycoproteins
  • Proteinase Inhibitory Proteins, Secretory
  • RNA, Messenger
  • SPINT1 protein, human
  • SPINT2 protein, human
  • KLK14 protein, human
  • Kallikreins