Sánchez-Sanz, GoarGoarSánchez-SanzTywoniuk, BartłomiejBartłomiejTywoniukMatallanas, DavidDavidMatallanasRomano, DavidDavidRomanoNguyen, Lan K.Lan K.NguyenKholodenko, Boris N.Boris N.KholodenkoRosta, EdinaEdinaRostaKolch, WalterWalterKolchBuchete, Nicolae-ViorelNicolae-ViorelBuchete2018-09-042018-09-042016 the A2016-10-07PLoS Computational Biologyhttp://hdl.handle.net/10197/9462We model the conformational changes and protein-protein interactions of enzymes involved in signaling along the Hippo pathwaya key molecular mechanism that controls the process of programmed cell death in eukaryotic cells, including cells affected by cancer. Combining modern computational modeling techniques with experimental information from X-ray crystallography and systems biology studies, can unveil detailed molecular interactions and lead to novel drugs. Here, we study the atomistic mechanisms and interactions between MST2 and RASSF-type kinases, through their respective SARAH domains highly conserved, long, terminal α-helices, which play essential roles in the activation of MST kinases and, therefore, in modulating apoptosis. In spite of their key roles in mediating cell signaling pathways, there is little structural information available for the RASSF SARAH domains and their dimerization with the MST2 SARAH domains. In particular, the RASSF1A crystal structure is not available yet. Here, we model, refine and validate atomistic structural models of dimers of the RASSF1A and MST2 SARAH domains, studying the interaction and the dynamic behavior of these molecular complexes using homology modeling, docking and full atomistic molecular dynamics simulations. Experimentally, we validate our approach by designing a novel peptide that can disrupt effectively MST2 homo and hetero SARAH dimers.enThis is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.Competing protein interactionsSARAH domainsSignaling switchesApoptosisCell fate decisionMolecular dynamicsJournal Article121010.1371/journal.pcbi.10050512017-10-17https://creativecommons.org/licenses/by-nc-nd/3.0/ie/