LAUSR

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.