Analysis of the HIV-2 protease’s adaptation to various ligands: characterization of backbone asymmetry using a structural alphabet

Abstract

The HIV-2 protease (PR2) is a homodimer of 99 residues with asymmetric assembly and binding various ligands. We propose an exhaustive study of the local structural asymmetry between the two monomers of all available PR2 structures complexed with various inhibitors using a structural alphabet approach. On average, PR2 exhibits asymmetry in 31% of its positions—i.e., exhibiting different backbone local conformations in the two monomers. This asymmetry was observed all along its structure, particularly in the elbow and flap regions. We first differentiated structural asymmetry conserved in most PR2 structures from the one specific to some PR2. Then, we explored the origin of the detected asymmetry in PR2. We localized asymmetry that could be induced by PR2’s flexibility, allowing transition from the semi-open to closed conformations and the asymmetry potentially induced by ligand binding. This latter could be important for the PR2’s adaptation to diverse ligands. Our results highlighted some differences between asymmetry of PR2 bound to darunavir and amprenavir that could explain their differences of affinity. This knowledge is critical for a better description of PR2’s recognition and adaptation to various ligands and for a better understanding of the resistance of PR2 to most PR2 inhibitors, a major antiretroviral class.

The Symmetric Difference Distance: A New Way to Evaluate the Evolution of Interfaces along Molecular Dynamics Trajectories; Application to Influenza Hemagglutinin

“…This is in agreement with the maximal donor-acceptor distance established in [34] at 3.9 Å. It is significantly smaller than the 4.5 Å cutoff distance between non-H atoms used by other authors [33,35,36].…”

“…PPIC was shown to be effective to compute interfaces on a database of 1050 protein homo-and hetero-dimers ( [29]; data from [32]). It was used to compute HIV2 protease-ligand interfaces ( [29]; data from [33]). For both datasets, it was observed that the best agreement between the interface calculations produced on heavy atoms by PPIC and those produced by the cutoff method occurred for a cutoff near 3.6-3.7 Å (see Figure 1 in [29]).…”

Characterization of HIV-2 Protease Structure by Studying Its Asymmetry at the Different Levels of Protein Description

“…The link between PR2 specificity for PIs and its structural asymmetry is, to date, imperfectly characterized. Structural asymmetry has been previously detected in PR2, particularly in the tail, elbow and flap regions [14][15][16][17][18]. In a recent work, we detected structural asymmetry in the 18 available crystallographic structures of the PR2 dimer in complex with diverse ligands [18].…”

“…Structural asymmetry has been previously detected in PR2, particularly in the tail, elbow and flap regions [14][15][16][17][18]. In a recent work, we detected structural asymmetry in the 18 available crystallographic structures of the PR2 dimer in complex with diverse ligands [18]. We located positions having different backbone conformations between the two chains in the 18 PR2 dimer structures using the HMM-SA structural alphabet (Hidden Markov Model-Structural Alphabet) [19].…”

“…In this study, we focused on deeper analysis of asymmetry of the unbound PR2, i.e., not complexed with a ligand, by taking into account three levels of the characterization of PR2 structure: local conformations, accessible surface area, and flexibility. Firstly, we analyzed the structural asymmetry in the crystallographic structure of the unbound PR2 by detecting residues presenting different local conformations using the HMM-SA-based approach that we previously developed [18]. Secondly, we analyzed PR2 asymmetry by focusing on residue accessible surface area (ASA) that is used to define surface exposed residues often crucial for interactions with other proteins and buried residues contributing in the stability of the tertiary structure [20].…”