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

Christian Solís-Calero; Hernandes F. Carvalho

doi:10.1002/cbin.10839

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

Christian Solís-Calero, Hernandes F. Carvalho

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4 Scopus citations

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.

Original language	English
Pages (from-to)	1246-1264
Number of pages	19
Journal	Cell Biology International
Volume	41
Issue number	11
DOIs	https://doi.org/10.1002/cbin.10839
State	Published - Nov 2017

Bibliographical note

Funding Information:
The authors are grateful to Centro Nacional de Processa-mento de Alto Desempenho em São Paulo (CENAPAD-SP), and Laboratório de Genômica e Proteômica of the Universidade Estadual de Campinas (UNICAMP), for granting access to their computational facilities. The authors also thank also BioSolveIT GmbH (St. Augustin, Germany) for providing the program PoseView. This manuscript is part of the series on Prostate Cell Biology, in commemoration of the 20th anniversary of the publication by Carvalho and Line (1996) Cell Biol Int 20: 809. This study was funded by grants from FAPESP (Brazil) (Grant nr 2009/16150-6) and CNPq.

Publisher Copyright:
© 2017 International Federation for Cell Biology

Keywords

HAI-1
HAI-2
HGF/Met signaling
KLK14
molecular dynamics simulations
prostate cancer

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10.1002/cbin.10839

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

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",

author = "Christian Sol{\'i}s-Calero and Carvalho, {Hernandes F.}",

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N2 - 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.

AB - 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.

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

Abstract

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Keywords

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