Uncertainty of protein-ligand binding constants: asymmetric confidence intervals versus standard errors

Paketurytė, V. and Petrauskas, V. and Zubrienė, A. and Abian, O. and Bastos, M. and Chen, W.-Y. and Moreno, M.J. and Krainer, G. and Linkuvienė, V. and Sedivy, A. and Velazquez-Campoy, A. and Williams, Mark A. and Matulis, D. (2021) Uncertainty of protein-ligand binding constants: asymmetric confidence intervals versus standard errors. European Biophysics Journal with Biophysics letters 50 , pp. 661-670. ISSN 0175-7571.

Abstract

Equilibrium binding constants (Kb) between chemical compounds and target proteins or between interacting proteins provide a quantitative understanding of biological interaction mechanisms. Reporting uncertainties of measured experimental parameters are critical for decision making in many scientific areas, e.g., in lead compound discovery processes and in comparing computational predictions with experimental results. Uncertainties in measured Kb values are commonly represented by a symmetric normal distribution, often quoted in terms of the experimental value plus-minus the standard deviation. However, in general the distributions of measured Kb (and equivalent Kd) values and the corresponding free energy change DeltaGb are all asymmetric to varying degree. Here, using a simulation approach, we illustrate the effect of asymmetric Kb distributions within the realm of isothermal titration calorimetry (ITC) experiments. Further we illustrate the known, but perhaps not widely appreciated, fact that when distributions of any of Kb, Kd and DeltaGb are transformed into each other their degree of asymmetry is changed. Consequently, we recommend that a more accurate way of expressing the uncertainties of Kb, Kd, and DeltaGb values is to consistently report 95% confidence intervals, in line with other author’s suggestions. The ways to obtain such error ranges are discussed in detail and exemplified for a binding reaction obtained by ITC.

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