A new and very promising strategy for HIV drug discovery consists in blocking the multiple functional interactions between HIV-1 integrase (IN) and its cellular cofactors. At present, this line of action is hindered by the absence of three-dimensional structures of IN in complex with any of them. In this article, we developed a full-length three-dimensional structure of IN, including the highly flexible terminal residues 270–288, which are not experimentally solved. Additionally, we built models of IN complexed to the human acetyltransferases GCN5 and p300 based on available structural and mutagenesis data. Then, we studied the dynamical behavior of these models by means of the Coarse-Grained Molecular Dynamics (CGMD) and Essential Dynamics (ED) to locate and characterize the nature of the largest collective motions. We found correlated motions involving distant regions of IN. Moreover, we found that these are influenced by the binding with the acetyltransferases (HATs). Taken together these findings suggest a way to affect the acetyltransferase binding by an allosteric type of inhibition and provide an important new approach for the drug design against HIV disease. Proteins 2009. © 2009 Wiley-Liss, Inc.