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Stability and Kinetic Properties of C5-Domain from Myosin Binding Protein C and its Mutants

Carlo Guardiani ^*, Fabio Cecconi  and Roberto Livi 

^* Centro Interdipartimentale per lo Studio delle Dinamiche Complesse, INFN Sezione di Firenze, Italy; INFM-CNR, Center for Statistical Mechanics and Complexity Istituto dei Sistemi Complessi (ISC-CNR), Rome, Italy; and Dipartimento di Fisica Università di Firenze, Centro Interdipartimentale per lo Studio delle Dinamiche Complesse, INFN Sezione di Firenze e INFM UdR Firenze, Italy

Correspondence: Address reprint requests to Fabio Cecconi, Tel.: 39-06-4993-7453; E-mail: cecconif{at}romal.infn.it.

The impact of three mutations of domain C5 from myosin binding protein C, correlated to Familial Hypertrophic Cardiomyopathy, has been assessed through molecular dynamics simulations based on a native centric protein modeling. The severity of the phenotype correlates with the shift in unfolding temperature determined by the mutations. A contact probability analysis reveals a folding process of the C5 domain originating in the region of DE and FG loops and propagating toward the area proximal to CD and EF loops. This suggests that mutation effects gain relevance in the proximity to the area where folding originates. The scenario is also confirmed by the analysis of the kinetics of 27 test mutations evenly distributed throughout the entire C5 domain.