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Department of Medicinal Chemistry and Institute for Structural Biology and Drug Discovery, Virginia Commonwealth University

Date of Submission

March 2015


Characterizing the nature of interaction between proteins that have not been experimentally co-crystallized requires a computational docking approach that can successfully predict the spatial conformation adopted in the complex. In this work, the Hydropathic INTeractions (HINT) force field model was used for scoring docked models in a data set of 30 high-resolution crystallographically characterized “dry” protein-protein complexes, and was shown to reliably identify native-like models. However, most current protein-protein docking algorithms fail to explicitly account for water molecules involved in bridging interactions that mediate and stabilize the association of the protein partners, so we used HINT to illuminate the physical and chemical properties of bridging waters and account for their energetic stabilizing contributions. The HINT water Relevance metric identified the ‘truly’ bridging waters at the 30 protein-protein interfaces and we utilized them in “solvated” docking by manually inserting them into the input files for the rigid body ZDOCK program. By accounting for these interfacial waters, a statistically significant improvement of ~24% in the average hit-count within the top-10 predictions the protein-protein dataset was seen, compared to standard “dry” docking. The results also show scoring improvement, with medium and high accuracy models ranking much better than incorrect ones. These improvements can be attributed to the physical presence of water molecules that alter surface properties and better represent native shape and hydropathic complementarity between interacting partners, with concomitantly more accurate native-like structure predictions.


© 2013 Wiley Periodicals, Inc. This is the peer reviewed version of the following article: Parikh, H. I. and Kellogg, G. E. (2014), Intuitive, but not simple: Including explicit water molecules in protein–protein docking simulations improves model quality. Proteins, 82: 916–932, which has been published in final form at doi:10.1002/prot.24466. This article may be used for non-commercial purposes in accordance With Wiley Terms and Conditions for self-archiving.

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VCU Medicinal Chemistry Publications