Thermal folding molecular dynamics simulations of the domain C5 of Myosin binding protein C were performed using a native-centric model to study the role of three mutations related to Familial Hypertrophic Cardiomyopathy. Mutation of Asn755 causes the largest shift of the folding temperature, and the residue is located in the CFGA′ β-sheet featuring the highest Φ-values. The mutation thus appears to reduce the thermodynamic stability in agreement with experimental data. The mutations on Arg654 and Arg668, conversely, cause little change in the folding temperature and they reside in the low Φ-value BDE β-sheet, so that their pathological role cannot be related to impairment of the folding process but possibly to the binding with target molecules. As the typical signature of Domain C5 is the presence of a longer and destibilizing CD-loop with respect to the other Ig-like domains, we completed the work with a bioinformatic analysis of this loop showing a high density of negative charge and low hydrophobicity. This indicates the CD-loop as a natively unfolded sequence with a likely coupling between folding and ligand binding.

Computational analysis of folding and mutation properties of C5 domain of Myosin binding protein C / C. GUARDIANI; F. CECCONI; R. LIVI. - In: PROTEINS. - ISSN 0887-3585. - STAMPA. - (2007), pp. 1313-1322.

Computational analysis of folding and mutation properties of C5 domain of Myosin binding protein C

LIVI, ROBERTO
2007

Abstract

Thermal folding molecular dynamics simulations of the domain C5 of Myosin binding protein C were performed using a native-centric model to study the role of three mutations related to Familial Hypertrophic Cardiomyopathy. Mutation of Asn755 causes the largest shift of the folding temperature, and the residue is located in the CFGA′ β-sheet featuring the highest Φ-values. The mutation thus appears to reduce the thermodynamic stability in agreement with experimental data. The mutations on Arg654 and Arg668, conversely, cause little change in the folding temperature and they reside in the low Φ-value BDE β-sheet, so that their pathological role cannot be related to impairment of the folding process but possibly to the binding with target molecules. As the typical signature of Domain C5 is the presence of a longer and destibilizing CD-loop with respect to the other Ig-like domains, we completed the work with a bioinformatic analysis of this loop showing a high density of negative charge and low hydrophobicity. This indicates the CD-loop as a natively unfolded sequence with a likely coupling between folding and ligand binding.
2007
1313
1322
C. GUARDIANI; F. CECCONI; R. LIVI
File in questo prodotto:
Non ci sono file associati a questo prodotto.

I documenti in FLORE sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificatore per citare o creare un link a questa risorsa: https://hdl.handle.net/2158/253568
Citazioni
  • ???jsp.display-item.citation.pmc??? ND
  • Scopus ND
  • ???jsp.display-item.citation.isi??? ND
social impact