A new methodology for the simulation of flexible protein–ligand interactions

Abstract

A methodology has been developed for the simulation of induced fit between a ligand and its target protein. It utilizes constrained molecular dynamics where atoms determined to be immobile from difference distance matrix studies are fixed. Application of this methodology to HIV-1 reverse transcriptase (RT) as the example target protein has demonstrated its robustness. Short simulation times are sufficient to achieve good refinement of docking poses resulting from exchange of structurally dissimilar inhibitors between crystal structures. Keywords

Investigation into the Extension of the Non-Nucleoside Reverse Transcriptase Binding Pocket

“…Using a superimposition set derived from previous work [6] the Ca atoms of 134 protein structures were overlayed in Discovery Studio (DS), version 2.55, [13] followed by extraction of their ligands. The superimposition set was derived from distance difference matrix analysis, using ProFlex, [5] which identifies pairs of Ca atoms that have minimal relative movement.…”

“…Our superimposition set of residues was originally developed by analysing 21 HIV-RT structures for regions of low relative variation between those 21 structures; [5] it was later expanded to 67 HIV-RT structures. [6] Our method is independent of the template (the structure used to align to), which means that any RT structure can be aligned to any other RT structure. This was confirmed here by aligning to two different templates and extracting the ligands of all structures, which resulted in two groups of the same ligands.…”

“…[5,6] Applying this methodology to the subset of publicly available RT crystal structures in the Protein Data Bank (PDB) [7] containing a ligand bound near the NNRTI pocket and then extracting those ligands, a detailed picture of the current binding region emerges, as illustrated in Fig. 1.…”