Using RosettaLigand for Small Molecule Docking into Comparative Models

Abstract

Computational small molecule docking into comparative models of proteins is widely used to query protein function and in the development of small molecule therapeutics. We benchmark RosettaLigand docking into comparative models for nine proteins built during CASP8 that contain ligands. We supplement the study with 21 additional protein/ligand complexes to cover a wider space of chemotypes. During a full docking run in 21 of the 30 cases, RosettaLigand successfully found a native-like binding mode among the top ten scoring binding modes. From the benchmark cases we find that careful template selection based on ligand occupancy provides the best chance of success while overall sequence identity between template and target do not appear to improve results. We also find that binding energy normalized by atom number is often less than −0.4 in native-like binding modes.

Ab initio structure determination from prion nanocrystals at atomic resolution by MicroED

“…The atomic arrangements solved by direct methods present a unique opportunity for further improvement of our current estimates of electron scattering factors. Our atomic structures include hydrogen atoms, which play a central role in many biochemical processes; knowing their positions has provided important insights into catalytic mechanisms (33,34) and greatly aids rational drug design (35). Lastly, by using direct methods, MicroED can also provide ab initio solutions for smallmolecule organic compounds, such as rare pharmaceutical polymorphs (36) and designer peptoids (37) that challenge other means of investigation.…”

Small-molecule ligand docking into comparative models with Rosetta

“…The study used crystallographic protein structures as inputs rather than comparative models. Kaufmann et al 42 demonstrated the predictive power of Rosetta ligand docking into Rosetta-built comparative models. In another study, RosettaLigand and AutoDock were used to dock 20 protein-ligand complexes 4 .…”

“…Throughout the manuscript, we will refer to dedicated benchmark papers relevant to the individual steps to serve as references for expected Rosetta performance. In addition, Kaufmann and Meiler 42 recently performed a benchmark of ligand docking into comparative models with Rosetta, to which the reader is encouraged to refer for further information concerning RosettaLigand’s performance for ligand docking into comparative models.…”

Open challenges in structure-based virtual screening: Receptor modeling, target flexibility consideration and active site water molecules description

“…The use of RosettaLigand [86,87] docking into homology models was benchmarked using nine protein-ligand complexes built during CASP8 [88], and other 21 additional complexes in order to expand the chemotype space. RosettaLigand found an acceptable native-like pose among the top ten scoring binding modes [89] in 21 out of 30 docking runs. It was also observed that docking performance depends more on template selection based on ligand occupancy than on target-template sequence identity.…”