Fast assessment of structural models of ion channels based on their predicted current-voltage characteristics

Abstract

Computational prediction of protein structures is a difficult task, which involves fast and accurate evaluation of candidate model structures. We propose to enhance single model quality assessment with a functionality evaluation phase for proteins whose quantitative functional characteristics are known. In particular, this idea can be applied to evaluation of structural models of ion channels, whose main function - conducting ions - can be quantitatively measured with the patch-clamp technique providing the current-voltage characteristics. The study was performed on a set of KcsA channel models obtained from complete and incomplete contact maps. A fast continuous electrodiffusion model was used for calculating the current-voltage characteristics of structural models. We found that the computed charge selectivity and total current were sensitive to structural and electrostatic quality of models. In practical terms, we show that evaluating predicted conductance values is an appropriate method to eliminate modes with an occluded pore or with multiple erroneously created pores. Moreover, filtering models on the basis of their predicted charge selectivity results in a substantial enrichment of the candidate set in highly accurate models. In addition to being a proof of the concept, our function-oriented single model quality assessment tool can be directly applied for evaluation of structural models of strongly-selective protein channels. Finally, our work raises an important question whether a computational validation of functionality should not be included in the evaluation process of structural models, whenever possible.