Dimerization of Transmembrane Helices of Receptor Tyrosine Kinases: Assessing the Convergence of Coarse-Grained Molecular Dynamics Simulations

Abstract

Signal transduction is essential for many biological processes, such as mitosis, cell regeneration and differentiation. The transmembrane (TM) domains of many signalling proteins are known to play an essential part in these processes, focussing structural and biophysical studies on transmembrane helix dimers. This is especially true of the receptor tyrosine kinase (RTK) family, for which many mutations are implicated in diseases including e.g. breast cancer, myasthenia gravis, and achondroplasia. Structures of a number of transmembrane helix dimers have been solved using solution NMR applied to peptide/detergent complexes, but many of these transmembrane helix dimers remain uncharacterised. A multiscale Molecular Dynamics (MD) simulation approach can yield models of comparative accuracy to NMR structures, making it a valuable tool to use for systems where the helix dimer structure is still unknown. The challenge then arises in determining the number of courage-grained (CG-MD) simulations needed to converge upon representative structures of the dimer, which can then be refined by converting to atomistic representation and simulated to compare with potential NMR structures. Here, an iterative jackknife approach is used to assess the convergence of CG-MD simulations, using the well-characterized helix dimer system of ErbB1. This approach will be illustrated for the transmembrane helix dimer of the RTK Muscle-Specific Kinase, whose transmembrane helix remains uncharacterised.