Molecular Dynamics Simulations of Human Frataxin: Insights in the Role of the Atypical C- terminal Peptide.

ERNESTO A ROMÁN; JAVIER SANTOS

Universidad Nacional de Quilmes, Buenos Aires

Congreso; Primera reunión de la Sociedad Argentina de Bioinformática; 2010

<!-- /* Font Definitions */ @font-face {font-family:"Cambria Math"; panose-1:2 4 5 3 5 4 6 3 2 4; mso-font-charset:0; mso-generic-font-family:roman; mso-font-pitch:variable; mso-font-signature:-1610611985 1107304683 0 0 159 0;} @font-face {font-family:Calibri; panose-1:2 15 5 2 2 2 4 3 2 4; mso-font-charset:0; mso-generic-font-family:swiss; mso-font-pitch:variable; mso-font-signature:-1610611985 1073750139 0 0 159 0;} /* Style Definitions */ p.MsoNormal, li.MsoNormal, div.MsoNormal {mso-style-unhide:no; mso-style-qformat:yes; mso-style-parent:""; margin-top:0cm; margin-right:0cm; margin-bottom:10.0pt; margin-left:0cm; line-height:115%; mso-pagination:widow-orphan; font-size:12.0pt; mso-bidi-font-size:11.0pt; font-family:"Times New Roman","serif"; mso-fareast-font-family:Calibri; mso-fareast-theme-font:minor-latin; mso-bidi-font-family:"Times New Roman"; mso-bidi-theme-font:minor-bidi; mso-fareast-language:EN-US;} .MsoChpDefault {mso-style-type:export-only; mso-default-props:yes; font-size:12.0pt; mso-ansi-font-size:12.0pt; mso-fareast-font-family:Calibri; mso-fareast-theme-font:minor-latin; mso-bidi-font-family:"Times New Roman"; mso-bidi-theme-font:minor-bidi; mso-fareast-language:EN-US;} .MsoPapDefault {mso-style-type:export-only; margin-bottom:10.0pt; line-height:115%;} @page Section1 {size:612.0pt 792.0pt; margin:70.85pt 3.0cm 70.85pt 3.0cm; mso-header-margin:36.0pt; mso-footer-margin:36.0pt; mso-paper-source:0;} div.Section1 {page:Section1;} --> Friedreich Ataxia (FA) is a progressive hereditary autosomal disease of children and adolescents and is characterized by neurological impairment and cardiomyopathy. It is caused by deficiency in the expression of frataxin protein (FXN) and by mutations that alter its stability. The oxidative stress caused by the increasing hydroxyl radicals produced by Fenton reaction and deficiency of iron-sulfur containing proteins are the proposed pathogenic mechanism in FA, as FXN is imported into the mitochondria where it is capable of sequester high quantities of Fe metal ion and acts like a Fe chaperone. Quaternary structure of yeast FXN (yFXN), an homopolymer of 24 subunits, is induced by iron. However, in the case of hFXN, this does not occur. The 3D structure of human FXN (hFXN) in its monomeric version is well known by NMR and X-ray crystallography. Variations in the C-terminal region correlate with the conformation stability of different homologues. However, we do not know which the molecular determinants are. In addition, we do not know which the importance of this region is in the folding process. In this way, it is necessary a detailed study of this region to understand its role as a structure module. In this work we decided to explore the role of the C-terminal peptide (C-T) on FXN stability. Our working hypothesis is that folding of human FXN depends on the formation of a cooperative tertiary unit based on the interaction between α-helix 1, α-helix 2, and peptide C-T (α-unit). In this way, we wish to establish which are the consequences of FXN truncation on its conformational flexibility. Our approach involves molecular dynamics simulation (MDS) and bioinformatics as the first steps to explore this problem and to outline the base of future experiments in our lab. Here, we compared results of MDS obtained for hFXN and a hFXN variant truncated in their 15 C-terminal residues  with results obtained for the distant homologue subunit NQO15 of respiratory complex I from Thermus thermophilus.