Deciphering Metastable EphA1 Transmembrane Helices Association using PMF Calculations and Multiscale Molecular Dynamics Simulations

Abstract

The association of transmembrane helices plays a significant role in the signalling of receptor tyrosine kinases. Recently the structures of the transmembrane domain of EphA1, which is a receptor tyrosine kinase implicated in a variety of cancers, were obtained via NMR spectroscopy [1]. Recent studies present the existence of multiple possible interaction modes for EphA1 which has lead to the suggestion that this system is governed by the rotation-coupled activation mechanism, with packing via different interaction motifs corresponding to active and inactive states of the dimers.To investigate further these results we performed potential of mean force (PMF) calculations for the association of the transmembrane helices of the receptor tyrosine kinases EphA1 using coarse-grained (CG) molecular dynamics calculations. The resulting profiles suggest two stable or metastable states for this system, consistent with the idea of a rotation-coupled activation mechanism. The most stable state for EphA1 involves a right-handed dimer interacting via an N-terminal glycine zipper motif, consistent with a recent structure from NMR spectroscopy. Interestingly the second state involves a left-handed dimer with interacting residues different from the glycine zipper. Analysis of unrestrained CG molecular dynamics based on the NMR structure of this dimer seems correlate these two states. The final analysis based on all atom simulations for the most representative structures of CG MDs give also valuable details for these interactions. So, multiscale molecular dynamics and PMF calculations shed a new light of the dynamical behaviour of such a system.Reference:1.Bocharov EV, Mayzel ML, Volynsky PE, Goncharuk MV, Ermolyuk YS, et al. (2008) Spatial structure and pH-dependent conformational diversity of dimeric transmembrane domain of the receptor tyrosine kinase EphA1. J Biol Chem 283: 29385-29395. doi:10.1074/jbc.M803089200.