Conformational states of HAMP domains interacting with sensory rhodopsin membrane systems: an integrated all-atom and coarse-grained molecular dynamics simulation approach

Abstract

Understanding the downstream signaling mechanism of sensory rhodopsin and its cognate transducer complex (srII–htrII) has long been a challenge in the field of photoreceptor research. Here, an integration of all-atom and coarse-grained (CG) molecular dynamics (MD) simulations in different srII–htrII complex states is carried out. It is shown that the cytoplasmic four-helix HAMP dimer gives rise to a gear-box model interaction with discrete hydrophobic packing in Natronomonas pharaonis (Np). Structural analysis in all-atom and CG-MD reveals a stable conformational state in the physiological environment (323 K and 1.15 M salt). Comparative analysis in the ground and intermediate state conformations reveals substantial inter-HAMP interactions in the intermediate state with uniform clockwise (+10° to +30°) and counterclockwise (−20° to −40°) rotations in the α1 helix and the α2 helix of the monomer, respectively. Low temperature and low salt environments (283 K and 0.15 M) significantly affect srII–htrII binding affinity in both states with unusual helix bending. The distinguished control cable, knob-into-holes packing and piston-like movements in HAMP helices are found in the intermediate state complex. The N-terminal htrII (159 residues) coupled with srII yields a binding energy (ΔG_bind) of −309.22, −436.53 and −331.11 kJ mol⁻¹ in the MM/PBSA calculation for the NphtrII homodimer, the NpsrII–htrII ground state conformation and the NpsrII–htrII intermediate state conformation, respectively. Only the HAMP1 domain shows a very low ΔG_bind value (−21.03 kJ mol⁻¹) for the ground state in comparison to that for the intermediate state (−54.68 kJ mol⁻¹). The structural analysis highlights the key residues that include Y199^srII, T189^srII, E43^htrII, T86^htrII, M100^htrII, E116^htrII, E126^htrII and S130^htrII for complex stabilization and signal transduction.