Getting Deeper into the Molecular Events of Heme Binding Mechanisms : A Comparative Multi-level Computational Study of HasAsm and HasAyp Hemophores
Tiessler-Sala, Laura (Universitat Autònoma de Barcelona. Departament de Química)
Sciortino, Giuseppe (Universitat Autònoma de Barcelona. Departament de Química)
Alonso-Cotchico, Lur (Universitat Autònoma de Barcelona. Departament de Química)
Masgrau, Laura (Universitat Autònoma de Barcelona. Departament de Química)
Lledós, Agustí (Universitat Autònoma de Barcelona. Departament de Química)
Maréchal, Jean-Didier (Universitat Autònoma de Barcelona. Departament de Química)

Data:	2022
Resum:	Many biological systems obtain their activity by the inclusion of metalloporphyrins into one or several binding pockets. However, decoding the molecular mechanism under which these compounds bind to their receptors is something that has not been widely explored and is a field with open questions. In the present work, we apply computational techniques to unravel and compare the mechanisms of two heme-binding systems, concretely the HasA hemophores from Gram negative bacteria Serratia marcescens (HasAsm) and Yersinia pestis (HasAyp). Despite the high sequence identity between both systems, the comparison between the X-ray structures of their apo and holo forms suggests different heme-binding mechanisms. HasAyp has extremely similar structures for heme-free and heme-bound forms, while HasAsm presents a very large displacement of a loop that ultimately leads to an additional coordination to the metal with respect to HasAyp. We combined Gaussian accelerated molecular dynamics simulations (GaMDs) in explicit solvent and protein-ligand docking optimized for metalloligands. GaMDs were first carried out on heme-free forms of both hemophores. Then, protein-ligand dockings of the heme were performed on cluster representatives of these simulations and the best poses were then subjected to a new series of GaMDs. A series of analyses reveal the following: (1) HasAyp has a conformational landscape extremely similar between heme-bound and unbound states with no to limited impact on the binding of the cofactor, (2) HasAsm presents as a slightly broader conformational landscape in its apo state but can only visit conformations similar to the X-ray of the holo form when the heme has been bound. Such behavior results from a complex cascade of changes in interactions that spread from the heme-binding pocket to the flexible loop previously mentioned. This study sheds light on the diversity of molecular mechanisms of heme-binding and discusses the weight between the pre-organization of the receptor as well as the induced motions resulting in association. Heme-containing enzymes and proteins are important for many biological and biotechnological processes. However, very little is known about heme-binding mechanisms. To shed light on this, we report a multi-level approach combining Gaussian accelerated molecular dynamics and protein−ligand dockings optimized for metallic moieties. The protocol unveils the difference in heme recruitment between HasAsm and HasAyp hemophores and shows its possible applicability to other heme-binding proteins.
Ajuts:	Agencia Estatal de Investigación PID-2020-116861GB-I00 Ministerio de Ciencia e Innovación FPU18/05895 Ministerio de Ciencia e Innovación PGC2018-098592-B-100
Nota:	Altres ajuts: acords transformatius de la UAB
Drets:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Publicat a:	Inorganic chemistry, Vol. 61, Issue 43 (October 2022) , p. 17068-17079, ISSN 1520-510X

DOI: 10.1021/acs.inorgchem.2c02193
PMID: 36250592

12 p, 11.9 MB

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