Affiliation:
1. Department of Physiology and Biophysics, Albert Einstein College of Medicine, 1300 Morris Park Ave., Bronx, NY 10461, USA
Abstract
Cardiac Troponin T (cTnT) is a central modulator of thin filament regulation of myofilament activation. The lack of structural data for the TNT1 tail domain, a proposed α-helical region, makes the functional implications of the FHC mutations difficult to determine. Studies have suggested that flexibility of TNT1 is important in normal protein–protein interactions within the thin filament. Our groups have previously shown through molecular dynamics (MD) simulations that some FHC mutations, Arg92Leu (R92L) and Arg92Trp (R92W), result in increased flexibility at a critical hinge region 18 Angstroms distant from the mutation. To explain this distant effect and its implications for FHC mutations, we characterized the dynamics of wild type and mutational segments of cTnT using MD. Our data shows an opening of the helix between residues 105–110 in mutants. Consequently, the dihedral angles of these residues correspond to non-α-helical regions on Ramachandran plots. We hypothesize the removal of a charged residue decreases electrostatic repulsion between the point mutation and the surrounding residues resulting in local helical compaction. Constrained ends of the helix and localized compaction result in expansion within the nearest non-charged helical turn from the mutation site, residues 105–109.
Publisher
World Scientific Pub Co Pte Lt
Subject
Computational Theory and Mathematics,Physical and Theoretical Chemistry,Computer Science Applications
Cited by
18 articles.
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