Molecular dynamics simulations of human frataxin: insights in the role of the C-terminal peptide

ERNESTO A. ROMAN; JAVIER SANTOS

Universidad Nacional de Quilmes, Provincia de Buenos Aires, Argentina.

Congreso; Reunión Anual de la Sociedad Argentina de Bioinformática y Biología Computaciona; 2010

Sociedad Argentina de Bioinformática y Biología Computacional.

<!-- /* Font Definitions */ @font-face {font-family:"Book Antiqua"; panose-1:2 4 6 2 5 3 5 3 3 4; mso-font-charset:0; mso-generic-font-family:roman; mso-font-pitch:variable; mso-font-signature:647 0 0 0 159 0;} /* Style Definitions */ p.MsoNormal, li.MsoNormal, div.MsoNormal {mso-style-parent:""; margin:0cm; margin-bottom:.0001pt; mso-pagination:widow-orphan; font-size:12.0pt; font-family:"Times New Roman"; mso-fareast-font-family:"Times New Roman"; mso-fareast-language:ES;} @page Section1 {size:595.3pt 841.9pt; margin:70.85pt 3.0cm 70.85pt 3.0cm; mso-header-margin:35.4pt; mso-footer-margin:35.4pt; 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 on 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 is the importance of this region in cooperativity, folding process, and multimerization of FXN. In this way, it is necessary a detailed study of this region to understand its role as a structure module. In this project we decided to explore the role of the C-terminal peptide (C-T) on FXN stability. We hypothesize that folding of human FXN depends on the formation of a cooperative tertiary unit based on the interaction between a-helix 1, a-helix 2 and peptide C-T (a‑unit). In this way, we think that it is important to establish the consequences on conformational flexibility of each structure module of human FXN after truncation of C-T. It is important to understand whether this native-like ensemble of the truncated form has particular properties that differ from full length FXN and could explain particular aggregation properties of other members of FXN family. Our approach involves molecular dynamics simulation (MDS) as the first step to explore this problem and to outline the base of future experiments in our lab. Our results confirm the role of C-T on the stabilization of the cooperative a‑unit of human FXN. We suggest that multimerization process of hFXN may be conducted by the populating in solution a competent partially folded state. The absence of C-T may help to populate this conformation.