Input files for targeted MD and umbrella sampling of cardiac thin filament

The cardiac thin filament is comprised of F-actin, tropomyosin, and troponin (cTn). cTn is composed of three subunits: troponin C (cTnC), troponin I (cTnI), and troponin T (cTnT). To computationally study the effect of the thin filament on cTn activation events, we employed targeted molecular dynamics followed by umbrella sampling using a model of the thin filament to measure the thermodynamics of cTn transition events. Our simulations revealed that the thin filament causes an increase in the free energy required to open the cTnC hydrophobic patch and causes a more favorable interaction between this region and the cTnI switch peptide. Mutations to the cTn complex can lead to cardiomyopathy, a collection of diseases that present clinically with symptoms of hypertrophy or dilation of the cardiac muscle, leading to impairment of the heart's ability to function normally, and ultimately myocardial infarction or heart failure. Upon introduction of cardiomyopathic mutations to R145 of cTnI, we observed a general decrease in the free energy of opening the cTnC hydrophobic patch, which is on par with previous experimental results. These mutations also exhibited a decrease in electrostatic interactions between cTnI-R145 and actin-E334. After introduction of a small molecule to the wild-type cTnI-actin interface to intentionally disrupt intersubunit contacts, we successfully observed similar thermodynamic consequences and disruptions to the same protein-protein contacts as observed with the cardiomyopathic mutations. Computational studies utilizing the cTn complex in isolation would have been unable to observe these effects, highlighting the importance of using a more physiologically relevant thin filament model to investigate the global consequences of cardiomyopathic mutations to the cTn complex..DCD and .PSF files should be opened by a software that can read the data (PyMOL, Chimera, Maestro, etc). All other files can be opened in a text editor.Funding provided by: National Heart, Lung, and Blood InstituteCrossref Funder Registry ID: http://dx.doi.org/10.13039/100000050Award Number: R01 HL137015The data being submitted are just starting files to run all targeted molecular dynamics and umbrella sampling simulations of the cardiac thin filament. Files were created manually by the submitting author