Focused grid‐based resampling for protein docking and mapping

Abstract

The fast Fourier transform (FFT) sampling algorithm has been used with success in application to protein-protein docking and for protein mapping, the latter docking a variety of small organic molecules for the identification of binding hot spots on the target protein. Here we explore the local rather than global usage of the FFT sampling approach in docking applications. If the global FFT based search yields a near-native cluster of docked structures for a protein complex, then focused resampling of the cluster generally leads to a substantial increase in the number of conformations close to the native structure. In protein mapping, focused resampling of the selected hot spot regions generally reveals further hot spots that, while not as strong as the primary hot spots, also contribute to ligand binding. The detection of additional ligand binding regions is shown by the improved overlap between hot spots and bound ligands.

New additions to the ClusPro server motivated by CAPRI

“…This is not for the lack of trying: during the last two years we have developed and tested several refinement algorithms. In terms of computational efficiency, the most promising approach was local resampling of near‐native clusters on a denser grid . The method has been tested on 49 complexes using structures obtained by docking unbound protein pairs.…”

“…The method has been tested on 49 complexes using structures obtained by docking unbound protein pairs. The resampling increased the number of near‐native structures for 31 of the 49 complexes, in 19 cases by >50%, whereas the number of near‐native structures substantially decreased only in 5 cases . Since we generally had more near‐native structures than in the initial docking, we clustered these with a smaller clustering radius, and expected to find some cluster centers closer to the native structure.…”

“…In terms of computational efficiency, the most promising approach was local resampling of near-native clusters on a denser grid. 37 The method has been tested on 49 complexes using structures obtained by docking unbound protein pairs. The resampling increased the number of nearnative structures for 31 of the 49 complexes, in 19 cases by >50%, whereas the number of near-native structures substantially decreased only in 5 cases.…”

“…The resampling increased the number of nearnative structures for 31 of the 49 complexes, in 19 cases by >50%, whereas the number of near-native structures substantially decreased only in 5 cases. 37 Since we generally had more near-native structures than in the initial docking, we clustered these with a smaller clustering radius, and expected to find some cluster centers closer to the native structure. However, this was the case only for a few of the proteins studied, and generally the distances of clusters centers from the X-ray structure did not substantially change.…”

Protein docking refinement by convex underestimation in the low-dimensional subspace of encounter complexes

“…A successful strategy is to use Monte Carlo -based sampling 4 . An alternative method that resamples around low-energy PIPER structures has also been proposed 5 . A host of methods seek to leverage the funnel-like shape of the energy function 6 – 8 .…”