The effect of cofactor binding on the conformational plasticity of the biological receptors in Artificial Metalloenzymes : The case study of LmrR
Alonso-Cotchico, Lur (Universitat Autònoma de Barcelona. Departament de Química)
Rodríguez-Guerra Pedregal, Jaime (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:	2019
Resum:	The design of Artificial Metalloenzymes (ArMs), which result from the incorporation of organometallic cofactors into biological structures, has grown steadily in the last two decades and important new-to-Nature reactions have been reached. These type of exercises could greatly benefit from an understanding of the structural impact that the inclusion of organometallic moieties may have on the biological host. To date though, our understanding of this phenomenon is highly partial. This lack of knowledge is one of the elements that condition that first-generation ArMs generally display relatively poor catalytic profiles. In this work, we approach this matter by assessing the dynamics and stability of a series of ArMs resulting from the inclusion, via different anchoring strategies, of a variety of organometallic cofactors into the Lactococcal multidrug resistance regulator (LmrR) protein. To this aim, we coupled standard force field-based techniques such as Protein-Ligand Docking and Molecular Dynamics simulations with a variety of trajectory convergence analyses, capable of assessing both the stability and flexibility of the different systems under study upon the binding of cofactors. Together with the experimental evidence obtained in other studies, we provide an overview on how these changes can affect the catalytic outcomes obtained from the different ArMs. Fundamentally, our results show that the convergence analysis used in this work can assess how the inclusion of synthetic metallic cofactors in proteins can condition different structural modulations of their host. Those conformational modifications are key to the success of the desired catalytic activity and their proper identification can be wisely used to improve the quality and the rate of success of the ArMs.
Ajuts:	Agencia Estatal de Investigación CTQ2017-87889-P Agència de Gestió d'Ajuts Universitaris i de Recerca 2017/SGR-1323
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
Matèria:	Molecular modeling ; Artificial metalloenzymes ; Molecular dynamics ; Interactive analysis ; Cofactor binding ; Molecular plasticity
Publicat a:	Frontiers in chemistry, Vol. 7 (April 2019) , art. 211, ISSN 2296-2646

DOI: 10.3389/fchem.2019.00211
PMID: 31024897

12 p, 3.5 MB

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