Abstract
For many targets of pharmaceutical importance conformational changes of the receptor protein are relevant during the ligand binding process. A new docking approach, ReFlexIn (Receptor Flexibility by Interpolation), that combines receptor flexibility with the computationally efficient potential grid representation of receptor molecules has been evaluated on the retroviral HIV-1 (Human Immunodeficiency Virus 1) protease system. An approximate inclusion of receptor flexibility is achieved by using interpolation between grid representations of individual receptor conformations. For the retroviral protease the method was tested on an ensemble of protease structures crystallized in the presence of different ligands and on a set of structures obtained from morphing between the unbound and a ligand-bound protease structure. Docking was performed on ligands known to bind to the protease and several non-binders. For the binders the ReFlexIn method yielded in almost all cases ligand placements in similar or closer agreement with experiment than docking to any of the ensemble members without degrading the discrimination with respect to non-binders. The improved docking performance compared to docking to rigid receptors allows for systematic virtual screening applications at very small additional computational cost.
Highlights
Protein receptor molecules can undergo a variety of conformational changes upon complex formation with binding partners ranging from small side chain adjustments to global backbone conformational changes and even refolding of loop structures [1,2,3,4,5,6,7]
Rigid Receptor Docking The ReFlexIn approach [23] implemented in AutoDock represents receptor flexibility by interpolation between potential grids each representing a different conformation of the protein
The set of binders consisted of the 7 ligands taken from the complexes that were used to form the ensemble of receptor structures and an additional set of binders from other HIV-1 protease complexes
Summary
Protein receptor molecules can undergo a variety of conformational changes upon complex formation with binding partners ranging from small side chain adjustments to global backbone conformational changes and even refolding of loop structures [1,2,3,4,5,6,7]. In order to account for conformational changes of the receptor it is possible to represent the receptor by an ensemble of rigid structures and to either use each structure separately for sequential docking or switching between ensemble members employing a Monte Carlo (MC) approach [17,18,19,20]. The structures for such ensemble can be derived either computationally, e.g. by molecular dynamics (MD) simulations or using appropriate structural modelling methods. More sophisticated methods have been suggested which include, for example, approaches that apply an ensemble average or select a consensus receptor out of the ensemble [22]
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