Abstract:We describe the testing and release of AutoDock4 and the accompanying graphical user interface AutoDockTools. AutoDock4 incorporates limited flexibility in the receptor. Several tests are reported here, including a redocking experiment with 188 diverse ligand-protein complexes and a cross-docking experiment using flexible sidechains in 87 HIV protease complexes. We also report its utility in analysis of covalently bound ligands, using both a grid-based docking method and a modification of the flexible sidechain technique.

The global AIDS epidemic has claimed the lives of more than 20 million people since 1981. Another 10 million are now living with HIV and most of these are likely to develop AIDS over the course of the next decade. In spite of the various treatment protocols available, including the mainstream

The emergence and continuing global spread of the highly virulent avian influenza H5N1 has raised concerns of a possible human pandemic. 1 Several approved anti-influenza drugs effectively target the neuraminidase (NA), a surface glycoprotein that cleaves terminal sialic acid residues and facilitates the release of viral progeny from infected cells. 2 The first crystal structures of group-1 NAs in apo form and in complex with currently available drugs 3 revealed that although the binding pose of oseltamivir (Tamiflu) was similar to that seen in previous crystallographic complexes, 4,5 the 150-loop adopted a distinct conformation, opening a new cavity adjacent to the active site. This open form of the 150-loop was proposed as a new opportunity for drug design. 3 However, under certain crystallization conditions, the 150-loop was found to adopt the same closed conformation as previously seen in group-2 structures, suggesting a slow conformational change may occur upon inhibitor binding. 3 The possible transience of the 150-loop cavity and its proximity to the inhibitor-binding site underscores the importance of dynamic biophysical studies to complement static crystal structures in NA drug discovery efforts. Through explicitly solvated molecular dynamics (MD) simulations of the apo and oseltamivir-bound forms of tetrameric N1, here we show that the 150-loop is able to open into significantly wider conformations than seen in the crystal structures. We find this motion in the 150-loop is coupled to motion in the neighboring 430-loop, which expands the active site cavity even further. In addition, we see that the 150-loop approaches the closed conformation in simulations of the oseltamivir-bound system, suggesting that the loop switching motion may be more rapid than previously proposed.Two separate MD simulations were carried out using apo and oseltamivir-bound crystal structures. 3 The tetramer structures are exceptionally stable over the course of the 40 ns simulations (Supporting Information Figure S1). A principal components analysis over all the chains for both systems reveals that the monomer subunits within each tetramer sample different regions of configurational space, establishing that their motion can be considered independent of one another ( Figure S2). On average, the apo N1 exhibits slightly higher overall per residue C R rootmean-square fluctuation (rmsf) values than the oseltamivir-bound system ( Figure S3). Further analysis reveals that the residues exhibiting the largest rmsf differences between the two systems are located at least 5.0 Å distal to the catalytic pocket, suggesting that the largest conformational changes are due to motions of surface-exposed loops rather than local changes directly within the active site pocket.Most notably, the MD trajectories suggest that the 150-loop is even more flexible than observed in the crystal structures. Although we do not sample the completely closed conformation, salt bridge and hydrogen bond interactions between oseltamivir and residues Asp151 and Arg15...