BION-2: Predicting Positions of Non-Specifically Bound ions on Protein Surface by a Gaussian-based Treatment of Electrostatic Environment

Abstract

<jats:title>Abstract</jats:title> <jats:p><jats:bold>Background: </jats:bold>Ions play significant roles in biological processes - they may specifically bind to a protein site or bind non-specifically on its surface. Though, the role of specifically bound ions range from actively providing structural compactness via coordination of charge-charge interactions to numerous enzymatic activities, non-specifically surface-bound ions are also crucial to maintaining a protein’s stability, responding to pH and ion concentration changes and contributing to other biological processes. However, experimental determination of positions of non-specifically bound ions is not trivial since they may have low residential time and experience significant thermal fluctuation of their positions. <jats:bold>Results: </jats:bold>Here we report a new release of a computational method, the BION-2 method, that predicts positions of non-specifically surface-bound ions. The BION-2 utilizes the Gaussian-based treatment of ions within the framework of the modified Poisson-Boltzmann equation, that does not require a sharp boundary between the protein and water phase. Thus, the predictions are done by the balance of the energy of interaction between the protein charges and the corresponding ions, and the de-solvation penalty of the ions as they approach the protein. <jats:bold>Conclusions:</jats:bold> The BION-2 is tested against experimentally determined ion’s positions, with both X-ray and NMR determined positions, and it is demonstrated that it outperforms the old BION and molecular dynamics tools. The BION-2 is available as a web server as well.</jats:p>

Huntingtin: A Protein with a Peculiar Solvent Accessible Surface

“…In this region, direct electrostatic interactions may dominate protein–membrane interactions [ 13 ]. Very recently, another ion-binding site predictor, BION-2, became available [ 42 ], and by adopting the calcium ion modality, we could confirm that calcium-binding sites are not limited to HEAT domains and that two calcium-binding sites are located at the border of the 166–443 region (data not shown).…”

“…Some of these binding sites are lateral to a previously characterized membrane binding region of the protein ( Figure 6 F) [ 13 ]. Results are confirmed by adopting another predictor, BION-2 [ 42 ]. Considering that calcium ions can mediate protein–membrane interactions [ 38 ], we would like to propose in this paper that huntingtin–membrane interactions can also be mediated by calcium as a cofactor.…”

“…All the predicted interacting sites when variated may hamper functional interactions of huntingtin with other genes important for many biological processes to which it contributes and elicit different disorders. By exploring with eDGAR [ 42 ] ( (accessed on 28 December 2020)) the complex space of gene–disease relations and taking advantage of the 98 gene interactors, we were able to associate huntingtin to some 43 more diseases different from HD (data not shown).…”

“…BION-2 [ 42 ] is a recently released predictor that utilizes the Gaussian-based treatment of ions within the framework of the modified Poisson–Boltzmann equation.…”