**1. Introduction**

Molecular recognition is a fundamental phenomenon observed in all biological systems organisation ‒ proteins, nucleic acids and their complexes, cells and tissues. Molecular recognition is governed by specific attractive interactions between two or more partner molecules through non-covalent bonding such as hydrogen bonds, metal coordination, electrostatic effects, hydrophobic and van der Waals interactions. The partners – recep‐ tor(s) and substrate(s) or ligands ‒ involved in molecular recognition, exhibit molecular complementarity that can be adjusted over the recognition process. Competition and co‐ operation, the two opposite natural effects contributing to selective and specific recogni‐ tion between participating partners, are the basic principles of substrate/ligand/inhibitor or protein binding to its targets.

The tertiary structures of biological objects (proteins and nucleic acids) are formed mainly by hydrogen bonds (enthalpic contributions) and by hydrophobic contacts (mostly entropic contributions). With a few exceptions, (e.g. ligand binding to the Ah receptor), the organisa‐ tion of ligand-protein complexes depends primarily on hydrogen bonding.

In the process of a ligand binding to its target the hydrogen bonds contribute to (i) the orien‐ tation of the substrates/ligands/inhibitors by a receptor, frequently associated with a confor‐ mational/structural adjustment of the interacting agents; (ii) the specific recognition of substrates/ligands/inhibitors and selectivity between sterically or structurally similar but bi‐ ochemically different species; (iii) the affinity of ligands/inhibitors ‒ the most decisive factor in drug design.

To describe the pharmacological properties of a given ligand or inhibitor, the knowledge of the site where the inhibitor is to bind with the target and of which interaction(s) control the specific recognition of the inhibitor by its target(s), represents a corner stone factor. Only a limited number of target-ligand molecular complexes have been characterized experimen‐

© 2013 Arora and Tchertanov; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2013 Arora and Tchertanov; licensee InTech. This is a paper distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

tally at the atomic level (X-ray or NMR analysis) [1]. Part of them describes the binding mode of therapeutically relevant ligands to biologically non-relevant and non-pertinent tar‐ gets (e.g., the HIV-1 integrase specific inhibitor RAL was published as a ligand fixed to the PFV intasome [2,3]). Consequently, a large quantity of reliable information on target-ligand binding is based on molecular docking methods which generate insights into the interac‐ tions of ligands with the amino acid residues in the binding pockets of the targets, and also predict the corresponding binding affinities of ligands [4]. The first step of a docking calcu‐ lation consists of the choice or generation/construction of the therapeutically appropriate target. Frequently the target modeling is a hard computational task which requires the ap‐ plication of sophisticated theoretical methods and constitutes a fascinating creative process.

in of the single-strand gaps between viral and target DNA molecules and ligation of the 3' ends of the vDNA to the 5'-ends of the hDNA (Figure 1 b). These two reactions are spatially and temporally separated and energetically independent: the 3'-processing takes place in the cytoplasm of the infected cells, whereas strand transfer occurs in the nuclei. They are cat‐ alyzed by the enzyme in different conformational and oligomerisation states: dimerization is required for the 3'-processing step [8,9], while tetrameric IN is believed to be required for

The HIV-1 Integrase: Modeling and Beyond http://dx.doi.org/10.5772/52344 379

(a) (b)

**Figure 1.** The HIV-1 replication cycle (a) and catalytic steps involved in the insertion of viral DNA into the human ge‐

The HIV-1 IN is a 288 amino acids enzyme (32 kDa) that consists in three structurally dis‐ tinct domains: (i) the N-terminal domain (NTD, IN1–49) with a non-conventional HHCC zincfinger motif, promoting protein multimerization; (ii) the central core domain (CCD, IN50–212) containing a canonical D,D,E motif performing catalysis and involved in DNA substrate rec‐ ognition [35]; (iii) the C-terminal domain (CTD, IN213–288), which non-specifically binds DNA and helps to stabilize the IN•vDNA complex [13]. Both integration steps, 3'-P and ST, in‐

Neither the structure of isolated full-length IN from HIV-1 nor that of IN complex with its DNA substrate has been determined. Nevertheless, the structures of the isolated HIV-1 do‐ mains or two domains were characterized by X-ray crystallography (34 structures) and NMR analysis (9 structures) [1]. NTD presented by 6 NMR structure solutions (1WJA, 1WJB, 1WJC, 1WJE, and 1WGF) [14-16] was classified by SCOP as the 'all alpha helix' structure and consists of four helices stabilized by a Zn2+cation coordinated with the HHCC motif (His12, His16, Cys40 and Cys43); the sequence from 43 to 49 residue are disordered (Figure 2). Structure of CTD was also characterised by NMR (3 deposited solutions (1IHV, 1IHW and 1QMC) [17,18]. According to the SCOP classification it presents the 'all beta strand' struc‐ ture and consists of five anti-parallel β-strands forming a β-barrel and adopting an SH3-like

volve the active site and the active site flexible loop formed by ten residues, IN140-149.

strand transfer [10-12].

nome (b) [6].

**2.2. Structural data**

fold (Figure 2).

Therefore, theoretical studies contribute first, to establish biologically valid models of the targets; second, through the use of these models, to the understanding of the protein func‐ tional properties; and finally to apply this data to rational drug design.

Here we compile and review the data on the molecular structure, properties and interac‐ tions of the HIV-1 integrase representing from one side, a characteristic example of a polyfunctional and complex biological object interacting with different viral and cellular partners and from another side, an attractive therapeutical target. We attempt to extract key messages of practical value and complement references with our own research of this viral enzyme. We characterized the structural and conformational features of Raltegravir (RAL), the first integrase specific inhibitor approved for the treatment of HIV/AIDS, and we ana‐ lyzed the factors contributing to RAL recognition by the viral targets.
