TY - JOUR
T1 - Uncertainty in protein–ligand binding constants
T2 - asymmetric confidence intervals versus standard errors
AU - Paketurytė, Vaida
AU - Petrauskas, Vytautas
AU - Zubrienė, Asta
AU - Abian, Olga
AU - Bastos, Margarida
AU - Chen, Wen Yih
AU - Moreno, Maria João
AU - Krainer, Georg
AU - Linkuvienė, Vaida
AU - Sedivy, Arthur
AU - Velazquez-Campoy, Adrian
AU - Williams, Mark A.
AU - Matulis, Daumantas
N1 - Publisher Copyright:
© 2021, European Biophysical Societies' Association.
PY - 2021/5
Y1 - 2021/5
N2 - Equilibrium binding constants (Kb) between chemical compounds and target proteins or between interacting proteins provide a quantitative understanding of biological interaction mechanisms. Reported 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 ΔGb 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 ΔGb 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 ΔGb values is to consistently report 95% confidence intervals, in line with other authors’ suggestions. The ways to obtain such error ranges are discussed in detail and exemplified for a binding reaction obtained by ITC.
AB - Equilibrium binding constants (Kb) between chemical compounds and target proteins or between interacting proteins provide a quantitative understanding of biological interaction mechanisms. Reported 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 ΔGb 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 ΔGb 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 ΔGb values is to consistently report 95% confidence intervals, in line with other authors’ suggestions. The ways to obtain such error ranges are discussed in detail and exemplified for a binding reaction obtained by ITC.
KW - Binding constant
KW - Confidence intervals
KW - Dissociation constant
KW - Isothermal titration calorimetry
KW - Log-normal distribution
KW - Standard error
UR - http://www.scopus.com/inward/record.url?scp=85104246384&partnerID=8YFLogxK
U2 - 10.1007/s00249-021-01518-4
DO - 10.1007/s00249-021-01518-4
M3 - 期刊論文
C2 - 33837826
AN - SCOPUS:85104246384
SN - 0175-7571
VL - 50
SP - 661
EP - 670
JO - European Biophysics Journal
JF - European Biophysics Journal
IS - 3-4
ER -