AB-INITIO MODELING AND MOLECULAR-DYNAMICS SIMULATION OF THE ALPHA(1B)-ADRENERGIC RECEPTOR ACTIVATION

This work describes the ab initio procedure employed to build an activ ation model for the alpha(1b)-adrenergic receptor (alpha(1b)-AR). The first version of the model was progressively modified and complicated by means of a many-step iterative procedure characterized by the emplo yment of experimental validations of the model in each upgrading step. a combined simulated (molecular dynamics) and experimental mutagenesi s approach was used to determine the structural and dynamic features c haracterizing the inactive and active states of alpha(1b)-AR. The late st version of the model has been successfully challenged with respect to its ability to interpret and predict the functional properties of a large number of mutants. The iterative approach employed to describe alpha(1b)-AR activation in terms of molecular structure and dynamics a llows further complications of the model to allow prediction and inter pretation of an ever-increasing number of experimental data. (C) 1998 Academic Press.