HIV-1 Integrase–DNA Interactions Investigated by Molecular Modelling.pdfVIP

Computational and Mathematical Methods in Medicine Vol. 9, Nos. 3–4, September–December 2008, 231–243 HIV-1 integrase–DNA interactions investigated by molecular modelling 1 1 C. Fenollar-Ferrer , V. Carnevale , S. Raugei and P. Carloni* International School for Advanced Studies and CNR-INFM Democritos, Trieste, Italy ( Received 28 February 2008; final version received 4 April 2008 ) HIV-1 integrase is the viral enzyme responsible for the insertion of the viral DNA into the host cell chromosome. This process occurs through two distinct biochemical reactions: the 30 -processing of the viral DNA and the transesterification reaction. Because experimental structural information on the reaction intermediate is not available, several molecular models have been developed. Unfortunately, none of the models of the enzyme–substrate complex is fully consistent with the available molecular biological data. We have constructed a new theoretical model based on mutagenesis experiments and cross-linking data, using a relatively accurate computational setup. The structural features of the model along with its limitations are discussed here. Keywords: HIV-1 integrase; molecular modelling; molecular dynamics; synaptic complex; protein–DNA interactions Introduction HIV-1 integrase plays an essential role in the retrovirus’ life cycle [11] and it is an established target of anti-AIDS therapy [1,50]. The enzyme inserts the reverse-transcribed viral DNA (vDNA, hereafter) into the host cell genome [51]. The process occurs via two nucleophilic reactions [56]: (i) a hydrolysis, performed by a Mg2 þ -activated water molecule, of dinucleotides (conserved across the retroviruses family to which HIV-1 belong [11