Monte Carlo simulations using PELE to identify a protein–protein inhibitor binding site and pose

Abstract

PELE prospectively unveils the binding site and mode of a protein–protein disruptor.

Insight into the mechanism of molecular recognition between human Integrin-Linked Kinase and Cpd22 and its implication at atomic level

“…Consequently, we decided to employ PELE (Protein Energy Landscape Surface), a relatively novel Monte Carlo algorithm, to investigate Cpd22 binding in a computationally affordable manner [ 34 ]. The PELE algorithm has been used successfully to determine the binding mode and location of several enzyme substrates, drugs and protein–protein inhibitors [ 35 , 36 ]. For PELE calculations, seven independent simulations were carried out starting from four different starting ligand positions in order to explore the ILK surface (Fig.…”

“…Protein Energy Landscape Exploration (PELE) is a Monte Carlo technique that includes protein structure prediction, thus allowing the exploration of potential binding sites via several sequential steps: ligand and/or protein perturbation followed by side rotamer sampling and energy minimization [ 34 ]. PELE has been used to find the small molecule binding site in proteins and to provide a dynamic perspective of substrate binding [ 35 , 36 ]. In the case of ILK, in order to determine the Cpd22 binding site, four simulations corresponding to different starting geometries were generated by placing the molecule over the refined ILK-apo surface manually, at a distance of approximately 5 Å, using UCSF Chimera 1.15 [ 52 ].…”

Insight into the mechanism of molecular recognition between human Integrin-Linked Kinase and Cpd22 and its implication at atomic level

“…Protein Energy Exploration (PELE) is a Monte Carlo technique that includes protein structure prediction, thus allowing the exploration of potential binding sites via several sequential steps: ligand and/or protein perturbation followed by side rotamer sampling and energy minimization [33]. PELE has been used to nd the small molecule binding site in proteins and to provide a dynamic perspective of substrate binding [34,35]. In the case of ILK, in order to determine the Cpd22 binding site, four simulations corresponding to different starting geometries were generated by placing the molecule over the re ned ILK-apo surface manually, at a distance of approximately 5 Å, using UCSF Chimera 1.15 [51].…”

“…Consequently, we decided to employ PELE (Protein Energy Landscape Surface), a relatively novel Monte Carlo algorithm, to investigate Cpd22 binding in a computationally affordable manner [33]. The PELE algorithm has been used successfully to determine the binding mode and location of several enzyme substrates, drugs and protein-protein inhibitors [34,35]. For PELE calculations, seven independent simulations were carried out starting from four different starting ligand positions in order to explore the ILK surface (Fig.…”

Recent PELE Developments and Applications in Drug Discovery Campaigns

“…This strategy has been helpful to determine ligand binding pathways, for example, in the nuclear hormone receptor [30] and in the vanillyl, alcohol oxidase [31]. Additionally, PELE's sampling could handle global explorations to identify binding sites around the protein surface as in this study where ligand binding interfaces for protein-protein inhibition in the flu virus hemagglutinin were identified [32]. The second package, despite the challenge it represents, offers a promising approach to the determination of absolute binding free energies, especially in systems with non-occluded binding sites such as urokinase or plasmin receptors where binding events can easily happen.…”