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Visualization of the numerical pose optimization with the JAMDA scoring function using the BFGS and the LSL-BFGS algorithm

<p>These videos demonstrate the behavior of two different optimization algorithms (BFGS and LSL-BFGS) during pose optimization using the JAMDA protein-ligand scoring function.</p> <p>Flachsenberg et al. (2020) (<a href="http://doi.org/10.1021/acs.jcim.0c01095" target="_blank" rel="noopener">10.1021/acs.jcim.0c01095</a>) describes the JAMDA protein-ligand scoring function and the LSL-BFGS algorithm.<br>The data for these videos stems from Experiment 5 in Flachsenberg et al. (2020). In this experiment, the crystal structure of a ligand was numerically optimized in the binding site with respect to the JAMDA scoring function to create the JAMDA-minimized crystal structure. The JAMDA-minimized crystal structure was randomly deflected to generate various starting poses for the numerical optimization.</p> <p>These videos demonstrate the behavior of two optimization algorithms (BFGS and LSL-BFGS) when optimizing one of the generated starting poses. The chosen example for the videos is a structure of ribonuclease A with a 5'-deoxy-5'-N-piperidinouridine inhibitor (PDB code 3d6q, <a href="https://doi.org/10.2210/pdb3D6Q/pdb" target="_blank" rel="noopener">10.2210/pdb3D6Q/pdb</a>, <a href="https://doi.org/10.1021/jm800724t" target="_blank" rel="noopener">10.1021/jm800724t</a>). Each of the videos shows all the intermediate steps the optimization algorithm takes until convergence.</p> <p>The main observation (that is discussed in detail in Flachsenberg et al. (2020)) is that the BFGS algorithm tends to take inappropriately large steps when clashes are present in the structure, resulting in unwanted binding mode changes. This is <em>not</em> the case for the LSL-BFGS algorithm.</p> <h3>Legend</h3> <p>For each iteration, the JAMDA score value, the RMSD to the JAMDA-minimized crystal structure (yellow), and the RMSD to the optimization's starting point (blue) are given. Furthermore, the gradient's norm (representing the main convergence criterion) is shown. In addition to the optimized ligand, also the JAMDA-minimized crystal structure (yellow) and the optimization's starting structure (blue) are shown.</p> <p><br>Each optimization algorithm is shown in two videos: In one video, the optimized ligand is colored by elements. Here, atoms with clashes (positive JAMDA scores) are marked with orange balls. In the other video, the atoms and bonds of the optimized ligand are colored by their individual JAMDA score.</p> <h3>Used Software</h3> <p>The snapshots of the optimization algorithms were rendered using PyMOL 3.0 (<a href="https://pymol.org/" target="_blank" rel="noopener">https://pymol.org/</a>) and further processed using the Pillow 10.4 Python library (<a href="https://doi.org/10.5281/zenodo.12606429" target="_blank" rel="noopener">10.5281/zenodo.12606429</a>). Videos were created from the individual snapshots using FFmpeg 7.0 (<a href="https://www.ffmpeg.org/" target="_blank" rel="noopener">https://www.ffmpeg.org/</a>).</p>