Computational studies of CXCR1, the receptor of IL-8/CXCL8, using molecular dynamics and electrostatics

The three-dimensional structure of IL-8/CXCL8 has been previously determined using NMR spectroscopy and X-ray crystallography, but the structure of the receptors for this chemokine has not been determined experimentally. We present here the development of a model for the structure of the IL-8/CXCL8 receptor CXCR1, using a combination of homology modeling and a molecular dynamics simulation. Based on this model, we discuss the analysis of structural, dynamic, and physicochemical properties of CXCR1. We focused on the role of pairwise ionic interactions in local structural stability of CXCR1 and the role of electrostatic potentials in recognition of CXCR1 with IL-8/CXCL8. We have performed theoretical mutations of six charged amino acids in CXCR1, which abolish binding as suggested by earlier experimental data, to shed light on the effect of charge on association ability. We propose that the observed loss of binding in the six CXCR1 mutants is owed to loss of local structural stability, rather than hindrance of the recognition process because of changes in the overall electrostatic properties of the receptor. Based on further structural analysis, we propose some mutations of charged residues involving ion pairs in different elements of transmembrane helices and extracellular loops, which are expected to alter the local structure and possibly affect binding.