Analyzing pathogenic mutations of C5 domain from cardiac myosin binding protein C through MD simulations.
The folding properties of wild type and mutants of domain C5 from cardiac myosin binding protein C have been investigated via molecular dynamics simulations within the framework of a native-centric and coarse-grained model. The relevance of a mutation has been assessed through the shift in the unfolding temperature, the change in the unfolding rate it determines and Phi-values analysis. In a previous paper (Guardiani et al. Biophys J 94:1403-1411, 2008), we performed Kinetic simulations on native contact formation revealing an entropy-driven folding pathway originating near the FG and DE loops. This folding mechanism allowed also a possible interpretation of the molecular impact of the three mutations, Arg14His, Arg28His and Asn115Lys involved in the Familial Hypertrophic Cardiomyopathy. Here we extend that analysis by enriching the mutant pool and we identify a correlation between unfolding rates and the number of native contacts retained in the transition state.
Cecconi
Fabio
F
INFM-SMC and Istituto dei Sistemi Complessi ISC-CNR, Via dei Taurini 19, 00185 Rome, Italy. cecconif@roma1.infn.it
Guardiani
Carlo
C
Livi
Roberto
R
D024741:Cardiomyopathy, Hypertrophic, Familial / Q000235:genetics*; D002352:Carrier Proteins / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism; D007700:Kinetics; D008958:Models, Molecular; D009154:Mutation; D011489:Protein Denaturation; D017510:Protein Folding; D017434:Protein Structure, Tertiary; D044366:Transition Temperature; D000099163:Myosin Binding Protein C
D002352:Carrier Proteins; D000099163:Myosin Binding Protein C