Induced-fit Effects Research Articles

Sensitivity of molecular docking to induced fit effects in influenza virus neuraminidase.

Many proteins undergo small side chain or even backbone movements on binding of different ligands into the same protein structure. This is known as induced fit and is potentially problematic for virtual screening of databases against protein targets. In this report we investigate the limits of the rigid protein approximation used by the docking program, GOLD, through cross-docking using protein structures of influenza neuraminidase. Neuraminidase is known to exhibit small but significant induced fit effects on ligand binding. Some neuraminidase crystal structures caused concern due to the bound ligand conformation and GOLD performed poorly on these complexes. A 'clean' set, which contained unique, unambiguous complexes, was defined. For this set, the lowest energy structure was correctly docked (i.e. RMSD < 1.5 A away from the crystal reference structure) in 84% of proteins, and the most promiscuous protein (1mwe) was able to dock all 15 ligands accurately including those that normally required an induced fit movement. This is considerably better than the 70% success rate seen with GOLD against general validation sets. Inclusion of specific water molecules involved in water-mediated hydrogen bonds did not significantly improve the docking performance for ligands that formed water-mediated contacts but it did prevent docking of ligands that displaced these waters. Our data supports the use of a single protein structure for virtual screening with GOLD in some applications involving induced fit effects, although care must be taken to identify the protein structure that performs best against a wide variety of ligands. The performance of GOLD was significantly better than the GOLD implementation of ChemScore and the reasons for this are discussed. Overall, GOLD has shown itself to be an extremely good, robust docking program for this system.

Hypothesis on the role of liganded states of proteins in energy transducing systems

In energy transducing systems the direction of energy transfer is proposed to be maintained by the synchronized turnovers of the conformational change of one protein coupling up to affect another. Catalysis by those systems implies, therefore, that under new space restrictions the groups of the transducing enzyme increase and decrease reactivity between themselves, with activatory and/or inhibitory ligands (H +, H 2O, metals, etc.) and with the electron shells of the reactant molecules. The exergonic reaction-dependent turnover of the forms of the enzyme within the transition complexes would be maintained, therefore, under asymmetric phase angles of conformational-dependent reactivity that would effectively restrict the microscopic reversibility of transducing systems. Some well known reactions, such as hemoglobin's Bohr effect, can be used to illustrate that microscopic (molecular) interactions subject to thermodynamic equilibria laws may similarly participate as driving forces in energy transducing systems. This would allow the thermodynamic description of the role of proton translocation as that of a modificatory force of the structural parameters of proteins. Similarly, the relationship between the liganded states of hemoglobin and its change in conformation has been used to develop an illustrative model relating changes in oxido-reduction of electron carriers to induced-fit effects leading to a sequence of ATPase forms in transition complexes which become stabilized as high energy intermediates under the constraints imposed by the membrane of energy transducing organelles.