ProPOSE: Direct Exhaustive Protein–Protein Docking with Side Chain Flexibility

Abstract

Despite decades of development, protein-protein docking remains a largely unsolved problem. The main difficulties are the immense space spanned by the translational and rotational degrees of freedom and the prediction of the conformational changes of proteins upon binding. FFT is generally the preferred method to exhaustively explore the translation-rotation space at a fine grid resolution, albeit with the trade-off of approximating force fields with correlation functions. This work presents a direct search alternative that samples the states in Cartesian space at the same resolution and computational cost as standard FFT methods. Operating in real space allows the use of standard force field functional forms used in typical non-FFT methods as well as the implementation of strategies for focused exploration of conformational flexibility. Currently, a few misplaced side chains can cause docking programs to fail. This work specifically addresses the problem of side chain rearrangements upon complex formation. Based on the observation that most side chains retain their unbound conformation upon binding, each rigidly docked pose is initially scored ignoring up to a limited number of side chain overlaps which are resolved in subsequent repacking and minimization steps. On test systems where side chains are altered and backbones held in their bound state, this implementation provides significantly better native pose recovery and higher quality (lower RMSD) predictions when compared with five of the most popular docking programs. The method is implemented in the software program ProPOSE (Protein Pose Optimization by Systematic Enumeration).

Computer-guided binding mode identification and affinity improvement of an LRR protein binder without structure determination

“…To overcome these bottlenecks, considerable effort has been made to develop alternative computational methods [ 8 , 9 ]. Despite some notable advances, however, computational determination of binding mode and in silico improvement of binding affinity remain challenging in general, and purely computational approaches have been insufficiently reliable for such purposes [ 10 – 13 ] and association energies [ 14 – 17 ]. Recent rounds of the Critical Assessment of Predicted Interactions (CAPRI) have also shown that current computational methods are not successful in identifying the actual binding mode [ 18 ].…”

What method to use for protein–protein docking?

“…In addition, further testing in CAPRI and other prediction experiments are needed in order to detect potential overtraining that can occur in machine learning with relatively small training sets. We note that a recent analysis found ClusPro more stable than other methods for docking unbound protein structures [28], most likely due to the final selection based on cluster size rather than scoring function value [29].…”

Redesigning An Antibody H3 Loop by Virtual Screening of A Small Library of Human Germline-Derived Sequences

“…Each antibody-antigen complex was prepared using the previously published protocol. 51 Each structure was downloaded from the PDB and the biomolecular transformation applied when present. Each antibody-antigen complex was processed with an automated preparation script to generate the initial structures.…”

“…On average, 50% of the loop conformations were removed. These loop conformations then had their hydrogen-bond network optimized using an in-house tool 51 followed by an energy minimization with AMBER FF99SB 55 using a distancedependent dielectric of 4, with the H3 loop atoms free to move and all other atoms fixed. The top-100 conformations per H3 stem according to their AMBER energy were retained.…”

“…The Talaris 2014 energy score was taken directly from the output of the loop ensemble generated previously. SIE was calculated after the hydrogen-bond network was optimized using an internal tool 51 and the H3 loop was energy-minimized with AMBER FF99SB 55 using a distance-dependent dielectric of 4, while its environment was fixed, and with the H3 loop heavy atoms restrained with a harmonic force constant of 1 kcal/mol/Å 2 .…”