HLA-DR beta 1*0101-HA and HLA-DR beta 1*0401-HA complexes are studied and compared by means of their computationally derived multipolar moments and electrostatic potentials. Changes in electrostatic potential are associated with definite pocket interaction profiles. Thus, Pocket I projects itself as an anchoring pocket for both complexes, in accordance with experimental results. While Pocket 4 has an anchoring profile in the HLA-DR beta 1*0101 allele, it presents itself as modulating pocket-peptide interactions in HLA-DR beta 1*0401. Pockets 6 and 7 both strongly contribute to allele specificity, with Pocket 7 being very important for HLA-DR beta 1*0401-HA. Pocket 9 acts as a "double purpose" interaction site for both alleles. It both projects itself as an anchoring pocket as well as modulating pocket-peptide interactions. (c) 2005 Elsevier Inc. All rights reserved.