NMR‐Guided Molecular Docking of a Protein–Peptide Complex Based on Ant Colony Optimization

Abstract

Standard docking approaches used for the prediction of protein-ligand complexes in the drug development process have problems identifying the correct binding mode of large flexible ligands. Herein we show how additional experimental data from NMR experiments can be used to predict the binding mode of a mucin 1 (MUC-1) pentapeptide recognized by the breast-cancer-selective monoclonal antibody SM3. Distance constraints derived from trNOE and saturation transfer difference NMR experiments are combined with the docking approach PLANTS. The resulting complex structures show excellent agreement with the NMR data and with a published X-ray crystal structure. The method was then further tested on two complexes in order to demonstrate its more general applicability: T-antigen disaccharide bound to Maclura pomifera agglutinin, and the inhibitor SBi279 bound to S100B protein. Our new approach has the advantages of being fully automatic, rapid, and unbiased; moreover, it is based on relatively easily obtainable experimental data and can greatly increase the reliability of the generated structures.

Bladder cancer detection using a peptide substrate of the 20S proteasome

“…A resolution [46] was used for docking simulations in the PLANTS program [47]. As there are no ligands in this structure, the b5/b6 subunits of mammalian 20S proteasome were overlapped with the crystal structure of the yeast 20S proteasome containing inhibitor molecule present in the b5/b6 active site [48] to give a reference for the initial structure of the peptidyl substrate.…”

NMR‐Assisted Molecular Docking Methodologies

“…The two molecules will transfer magnetization to each other through protein‐mediated spin diffusion (Figure 2). The relative orientation of the two ligands in the binding pocket is defined from the analysis of protein‐mediated intermolecular NOEs (see Korb et al 23. for more detailed theoretical introduction of the INPHARMA approach).…”

“…The information obtained by STD and trNOE experiments may be used as restrain in PLANTS molecular docking program 23. PLANTS is based on the Ant Colony Optimization (ACO) algorithm, a metaheuristic method belonging to swarm intelligence optimization methods 24.…”

Protein–ligand structure guided by backbone and side-chain proton chemical shift perturbations

“…CSPs have been shown to be able to find the ligand orientation in the protein binding site (McCoy and Wyss 2000) and to refine docking results (Cioffi et al 2008;Stark and Powers 2008;Cioffi et al 2009). The experimental data can also be included directly into the docking process to give docking results with experimental confidence (Dominguez et al 2003;Schieborr et al 2005;González-Ruiz and Gohlke 2009;Korb et al 2010).…”