  Thermal folding Molecular Dynamics simulations of the domain C5 from 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' beta-sheet featuring the highest Phi-values. The mutation
thus appears to reduce the thermodynamic stability in agreement with
experimental data. The mutations on Arg654 and Arg668, conversely, cause a
little change in the folding temperature and they reside in the low Phi-value
BDE beta-sheet, so that their pathologic 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
destabilizing 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.
