Coarse graining calcium pump ? membrane interactions: from salt bridges to interdomain rearrangements

BARRERA GUISASOLA, EXEQUIEL E.; PANTANO, SERGIO

Helsinki

Workshop; International workshop on biological membranes; 2018

Sarcoplasmic reticulum Ca 2+ -ATPase (SERCA) is a P-type ion transporter from skeletal muscle whose function consists in pumping Ca 2+ from the cytoplasm into the reticulum with the consequent muscle relaxation. Here, with the object of studying the structural and dynamic behavior of SERCA we performed molecular dynamics simulations at a coarse grained (CG) level. This kind of simplified representations allow the study of large size simulation boxes reaching multimicrosecond timescales.Starting configurations were generated embedding the SERCA reaction state E1-Ca 2+ (PDB:5XA7) in planar lipid bilayers and simulating them through 5μs at a temperature of 310K. Specific phospholipid-protein interactions reported from crystallographic structures [2] were monitored during the simulations. Basic residues and lipid phosphate groups formed salt bridges showing two classes of interactions: i) side chains emerging from the hydrophobic region and fixing particular phospholipids (i.e Lys262) and ii) side chains approaching the polar head groups from the cytoplasm and changing interacting partners (i.e. Arg110). Along the simulations the transmembrane domain tilted 35o, as observed in experimental data.This behavior was governed by a Trp belt distributed in the membrane-water interface. The effect of bilayer thickness over the stability of the transmembrane region was also studied employing bilayers of different composition. The absence of topological restraints in the force field [3] allowed us to reproduce conformational changes of the cytoplasmic domains associated with different intermediates along the functional cycle of the pump that has been previously characterized by FRET experiments [4]. Combined with experimental data, this in silico approach contributes to better understand the dynamic behavior of SERCA being also a promising strategy to study other transmembrane proteins