Abstract
Activity in many biological systems is mediated by pH, involving proton titratable groups with pKas in the relevant pH range. Experimental analysis of pH-dependence in proteins focusses on particular sidechains, often with mutagenesis of histidine, due to its pKa near to neutral pH. The key question for algorithms that predict pKas is whether they are sufficiently accurate to effectively narrow the search for molecular determinants of pH-dependence. Through analysis of inwardly rectifying potassium (Kir) channels and acid-sensing ion channels (ASICs), mutational effects on pH-dependence are probed, distinguishing between groups described as pH-coupled or pH-sensor. Whereas mutation can lead to a shift in transition pH between open and closed forms for either type of group, only for pH-sensor groups does mutation modulate the amplitude of the transition. It is shown that a hybrid Finite Difference Poisson-Boltzmann (FDPB) – Debye-Hückel continuum electrostatic model can filter mutation candidates, providing enrichment for key pH-coupled and pH-sensor residues in both ASICs and Kir channels, in comparison with application of FDPB alone.
Highlights
The dependence on pH of biological systems plays a key role in their structure and function [1]
It is apparent that the spread of predictions away from the diagonal is less for Finite Difference Poisson-Boltzmann/Debye-Hückel (FD/DH) than for Finite Difference Poisson-Boltzmann (FDPB)
Prediction and identification of candidate functional residues (CFRs) for pH-dependent properties of ion channels has been problematic for various reasons, including availability of relevant conformational data, interpretation of whether residues that alter pH50 when mutated are genuinely pH-sensors, and computational methods that generally over-estimate the number of acidic and basic ionisable groups with sufficiently large ΔpKas to bring their pKas into the physiological pH range
Summary
The dependence on pH of biological systems plays a key role in their structure and function [1]. Both normal and pathological processes are regulated by changes in the intracellular pH [2,3] and extracellular pH [4,5]. Two productive areas for linking theory and experiment have been protein folded state stability and catalysis. Each of these cases has their own problems.
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