Universität zu Köln

Rabipour, Mina ORCID: 0000-0003-3319-5302, Hassenrück, Floyd ORCID: 0000-0003-4772-5220, Pallaske, Elena, Röhrig, Fernanda ORCID: 0009-0006-8850-487X, Hallek, Michael ORCID: 0000-0002-7425-4455, Alvarez-Idaboy, Juan Raul ORCID: 0000-0002-2901-5412, Kramer, Oliver ORCID: 0000-0001-7607-1700 and Rebollido-Rios, Rocio ORCID: 0000-0002-8910-867X (2025). Allosteric Coupling in Full-Length Lyn Kinase Revealed by Molecular Dynamics and Network Analysis. International Journal of Molecular Sciences, 26 (12). MDPI. ISSN 1422-0067

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Abstract

[Artikel-Nr.: 5835] Lyn is a multifunctional Src-family kinase (SFK) that regulates immune signaling and has been implicated in diverse types of cancer. Unlike other SFKs, its full-length structure and regulatory dynamics remain poorly characterized. In this study, we present the first long-timescale molecular dynamics analysis of full-length Lyn, including the SH3, SH2, and SH1 domains, across wildtype, ligand-bound, and cancer-associated mutant states. Using principal component analysis, dynamic cross-correlation matrices, and network-based methods, we show that ATP binding stabilizes the kinase core and promotes interdomain coordination, while the ATP-competitive inhibitor dasatinib and specific mutations (e.g., E290K, I364N) induce conformational decoupling and weaken long-range communication. We identify integration modules and develop an interface-weighted scoring scheme to rank dynamically central residues. This analysis reveals 44 allosteric hubs spanning SH3, SH2, SH1, and interdomain regions. Finally, a random forest classifier trained on 16 MD-derived features highlights key interdomain descriptors, distinguishing functional states with an AUC of 0.98. Our results offer a dynamic and network-level framework for understanding Lyn regulation and identify potential regulatory hotspots for structure-based drug design. More broadly, our approach demonstrates the value of integrating full-length MD simulations with network and machine learning techniques to probe allosteric control in multidomain kinases.

Item Type:	Article
Creators:	Creators Email ORCID ORCID Put Code Rabipour, Mina UNSPECIFIED https://orcid.org/0000-0003-3319-5302 UNSPECIFIED Hassenrück, Floyd UNSPECIFIED https://orcid.org/0000-0003-4772-5220 UNSPECIFIED Pallaske, Elena UNSPECIFIED UNSPECIFIED UNSPECIFIED Röhrig, Fernanda UNSPECIFIED https://orcid.org/0009-0006-8850-487X UNSPECIFIED Hallek, Michael UNSPECIFIED https://orcid.org/0000-0002-7425-4455 UNSPECIFIED Alvarez-Idaboy, Juan Raul UNSPECIFIED https://orcid.org/0000-0002-2901-5412 UNSPECIFIED Kramer, Oliver UNSPECIFIED https://orcid.org/0000-0001-7607-1700 UNSPECIFIED Rebollido-Rios, Rocio UNSPECIFIED https://orcid.org/0000-0002-8910-867X UNSPECIFIED
URN:	urn:nbn:de:hbz:38-800046
Identification Number:	10.3390/ijms26125835
Journal or Publication Title:	International Journal of Molecular Sciences
Volume:	26
Number:	12
Number of Pages:	23
Date:	18 June 2025
Publisher:	MDPI
ISSN:	1422-0067
Language:	English
Faculty:	Central Institutions / Interdisciplinary Research Centers Faculty of Medicine
Divisions:	CECAD - Cluster of Excellence Cellular Stress Responses in Aging-Associated Diseases Faculty of Medicine > Innere Medizin > Klinik I für Innere Medizin - Hämatologie und Onkologie Zentrum für Molekulare Medizin
Subjects:	Medical sciences Medicine
Uncontrolled Keywords:	Keywords Language Lyn kinase ; allosteric regulation ; molecular dynamics simulations ; cancer-associated mutations ; machine learning ; dynamic cross-correlation matrix ; correlation network analysis ; multidomain kinases ; Src-family kinases English
['eprint_fieldname_oa_funders' not defined]:	Publikationsfonds UzK
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/80004