The role of solvent exclusion in the interaction between D124 and the metal site in SOD1: implications for ALS
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ORIGINAL PAPER
The role of solvent exclusion in the interaction between D124 and the metal site in SOD1: implications for ALS Rau´l Mera-Adasme • Carl-Mikael Suomivuori • Ange´lica Fierro • Janne Pesonen • Dage Sundholm
Received: 28 May 2013 / Accepted: 26 August 2013 / Published online: 13 September 2013 Ó SBIC 2013
Abstract Structural changes in the metal site of the copper–zinc superoxide dismutase (SOD1) are involved in the various mechanisms proposed for the pathogenesis of the SOD1-linked familial form of amyotrophic lateral sclerosis (ALS). Elucidating how the metal site of SOD1 can be disrupted by ALS-linked mutations is important for a better understanding of the pathogenesis of the disease and for developing more efficient treatments. Residue D124, a second-sphere ligand of the copper and zinc ions, is known from experimental studies to be essential for the integrity of the metal-site structure. In this work, we used density functional theory calculations and molecular dynamics simulations to elucidate which factors keep D124 attached to the metal site and how structural changes may disrupt the binding between D124 and the metal firstsphere ligands. The calculations show that D124 is kept
Electronic supplementary material The online version of this article (doi:10.1007/s00775-013-1039-8) contains supplementary material, which is available to authorized users. Present Address: R. Mera-Adasme (&) Chair of Theoretical Chemistry, Department of Chemistry, University of Munich (LMU), Butenanstr. 7, 81377 Munich, Germany e-mail: [email protected] R. Mera-Adasme C.-M. Suomivuori J. Pesonen D. Sundholm Department of Chemistry, University of Helsinki, P.O. Box 55, A.I. Virtanens Plats 1, 00014 Helsinki, Finland A. Fierro Departamento de Quı´mica Orga´nica, Facultad de Quı´mica, Pontificia Universidad Cato´lica de Chile, Santiago, Chile
attached to the metal site in a kinetic trap. The exclusion of solvent molecules by the electrostatic loop of the protein is found to create the binding of D124 to the metal site. The calculations also indicate that changes in the structure of the electrostatic loop of the protein can weaken the D124– metal site interaction, lowering the affinity of the zinc site for the metal. Destabilization of the electrostatic loop of SOD1 has been previously shown to be a common property of ALS-linked variants of the protein, but its role in the pathogenesis of SOD1-linked ALS has not been elucidated. Keywords Copper–zinc superoxide dismutase Amyotrophic lateral sclerosis Zinc
Introduction Amyotrophic lateral sclerosis (ALS) is a progressive and invariably fatal neurodegenerative disease that selectively attacks motor neurons. The pathogenesis of ALS is poorly understood [1]; therefore, there is no medical treatment that can prolong the life of the patient by more than a few months [2]. Most cases occur without any known reason and are thus termed sporadic ALS. Approximately 10 % of the cases are related to inherited mutations, and are therefore known as familial ALS (fALS). F
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