Computational characterization of the mutation impact on domain C5 of Myosin Binding Protein C

Carlo Guardiani; Fabio Cecconi; Roberto Livi

doi:10.1117/12.727673

21 June 2007 Computational characterization of the mutation impact on domain C5 of Myosin Binding Protein C

Carlo Guardiani, Fabio Cecconi, Roberto Livi

Proceedings Volume 6602, Noise and Fluctuations in Biological, Biophysical, and Biomedical Systems; 660209 (2007) https://doi.org/10.1117/12.727673
Event: SPIE Fourth International Symposium on Fluctuations and Noise, 2007, Florence, Italy

Abstract

Three mutations of domain C5 of Myosin Binding Protein C are involved in Familial Hypertrophic Cardiomyopathy. We assess their impact through Molecular Dynamics simulations within the framework of a native-centric coarse-grained model. We characterize the clinical relevance of a mutation by: the extent of temperature shift it induces in the unfolding transition, the increase of the kinetic unfolding rates with respect to the wild type, and by &Fgr;-value analysis. Further analysis of folding stages based on the evolution of native contact probabilities reveals an entropy-driven pathway originating in the protein region close to Res115 and ending up in the area of Res28. The mutation of the former residue thus appears to be responsible for an early interruption of the folding process, leaving the protein largely unstructured and yielding a serious impairment of cardiac function. Mut28, on the contrary, thwarts a late stage of folding when the protein is almost completely native-like, leading to a mild phenotype. A bio-informatic analisys of the long and destabilizing CD loop finally shows an excess of negative charge and a low hydrophobicity indicating a possible classification as a natively unfolded sequence. Accordingly, the folding mechanism is suggested to be coupled with binding with a specific ligand.

Citation Download Citation

Carlo Guardiani, Fabio Cecconi, and Roberto Livi "Computational characterization of the mutation impact on domain C5 of Myosin Binding Protein C", Proc. SPIE 6602, Noise and Fluctuations in Biological, Biophysical, and Biomedical Systems, 660209 (21 June 2007); https://doi.org/10.1117/12.727673

ACCESS THE FULL ARTICLE

INSTITUTIONAL
Select your institution to access the SPIE Digital Library.

SELECT YOUR INSTITUTION

PERSONAL
Sign in with your SPIE account to access your personal subscriptions or to use specific features such as save to my library, sign up for alerts, save searches, etc.

PERSONAL SIGN IN

No SPIE Account? Create one

PURCHASE THIS CONTENT

SUBSCRIBE TO DIGITAL LIBRARY

50 downloads per 1-year subscription

Members: $195

Non-members: $335 ADD TO CART

25 downloads per 1 - year subscription

Members: $145

Non-members: $250 ADD TO CART

PURCHASE SINGLE ARTICLE

Includes PDF, HTML & Video, when available

Members: $17.00

Non-members: $21.00 ADD TO CART

PROCEEDINGS
13 PAGES

DOWNLOAD PAPER SAVE TO MY LIBRARY

GET CITATION

RIGHTS & PERMISSIONS

Get copyright permission Get copyright permission on Copyright Marketplace

KEYWORDS

Proteins

Head

Thermodynamics

Molecules

Computer simulations

Image segmentation

Bioinformatics

Show All Keywords

Keywords/Phrases

Search In:

Publication Years