Numerical Errors and Chaotic Behavior in Docking Simulations

Abstract

This work examines the sensitivity of docking programs to tiny changes in ligand input files. The results show that nearly identical ligand input structures can produce dramatically different top-scoring docked poses. Even changing the atom order in a ligand input file can produce significantly different poses and scores. In well-behaved cases the docking variations are small and follow a normal distribution around a central pose and score, but in many cases the variations are large and reflect wildly different top scores and binding modes. The docking variations are characterized by statistical methods, and the sensitivity of high-throughput and more precise docking methods are compared. The results demonstrate that part of docking variation is due to numerical sensitivity and potentially chaotic effects in current docking algorithms and not solely due to incomplete ligand conformation and pose searching. These results have major implications for the way docking is currently used for pose prediction, ranking, and virtual screening.

Ligand Binding Mode Prediction by Docking: Mdm2/Mdmx Inhibitors as a Case Study

“…The chaotic behavior of docking simulations has been analyzed recently. 77 This complexity may explain our finding that sufficiently comprehensive conformation generation can “rescue” cross-docking failures.…”

Acoplamiento Molecular: Avances Recientes y Retos

“…Of note, the modules of protein preparation of different programs create slightly different output files having a direct impact on the docking results (Feher & Williams, 2012). Consequently, to compare results of docking (e.g., in virtual screening) it is strongly recommended to use the same preparation protocol for all the docking calculations.…”

“…This is because the preparation method can sometimes lead to errors in molecular description i.e., wrong connectivity, missing bonds, abnormal geometries, etc. Such errors tend to happen more often when converting between molecular formats and therefore are easily propagated (Feher & Williams, 2012). One most "use with caution" steps are modules implemented in some software packages that enable the user to prepare the structure of the ligand with one or few clicks.…”

About the concept of Chemical Space: a concerned reflection on some trends of modern scientific thought within theoretical chemical lore

“…One can safely say this last sentence about this docking lead travel, because recently docking has been proven to be some kind of random result generator [12]. This last reference providing the readers with evidence of a digital chaotic behavior of docking procedures currently employed.…”

“…In order to justify the randomly behaving docking procedures, the authors of reference [12] propose to rely on an intriguing question which arises in another reference [13], provided at the end of their study. Such a final statement appears as a final rescue boat or escape pod, trying to justify the obviously faulty docking programs behavior.…”