Hi,

For those interesting I’d like to provide an update. An adult male (39 years old) has been diagnosed with a severe progressive HCM (Septum thickness=38mm, LV=73/65mm, RV=37/32mm). A sample from this person was referred to Emory genetics laboratory for genetic testing and 50 genes were screened. A Gly54Ser mutation in LDB3 and two silent mutations in JPH2 (A208 and S555) have been identified. Gly54 is one of the highly conservative residues in ZASP PDZ domain thus both SIFT and PolyPhen-2 classified it as a damaging with a maximum score. FOLDX3.0 calculated that this mutation can be considered as a destabilizing too (dG=3.6) and I was surprised how well it predicted the effect of all known ZASP mutations. Further, we performed a massive molecular dynamics studies (dozens of hundred nanoseconds simulations) using battery of approaches (accelerated MD, classical MD, correlation, PCA and free energy analyses and etc.) on both the apo ZASP form and on the α-actinin2-ZASP complex, which has been created in advance. Our experience shows that nowadays the quality of the force fields and length of the simulations might give results that are comparable to the experimental one and if this approach is applied in a “good” way the information can be really considered as a confidential. Moreover, this methodology provides valuable structural information.

Anyway… both experimental and in silico data clearly show that the G54S, and presumably other mutations, in the ZASP’s PDZ domain is “damaging” and can be linked to HCM. This is due to the reduced ZASP binding to both α-actinin2 and the Calcium voltage channel and presumably the PKC and PKA hypertrophy pathways are involved. An abstract of our first paper about the subject (ZASP apo form), which is under review, can be found here:

https://www.researchgate.net/publication/260171217_Genetic_screen_and_in_silico_analyses_reveal_the_first_identified_mutation_in_ZASP_PDZ_domain_that_can_cause_hypertrophic_cardiomyopathy

Additional information, MRI pictures and etc. about the clinical condition of this individual and also MD movies are available on request. Any comments and discussions are welcome and will be helpful for me!

Regards,

Filip

Article Combination of Genetic Screening and Molecular Dynamics as a...