Molecular dynamics of the 5-HT1a receptor and ligands.

A 3-D model of the human 5-HT1a receptor was constructed from its amino acid sequence by computer graphics techniques, molecular mechanics calculations and molecular dynamics simulations. The model has seven alpha-helical membrane spanning segments, which form a central core containing a putative ligand binding site. Electrostatic potentials 1.4 A outside the water accessible surface were mainly negative on the synaptic side of the receptor model and at the postulated ligand binding site, and positive in the cytoplasmic domains. The negative electrostatic potentials around the synaptic domains indicate that positively charged ligands are attracted to the receptor by electrostatic forces. Molecular dynamics simulations of the receptor model with serotonin, ipsapirone, R(-)-methiothepin or S(+)-methiothepin in the central core suggested that up to 22 different amino acid residues may form a ligand binding pocket, and contribute to the specificity of ligand recognition and binding.