Dissecting the statistical properties of the linear extrapolation method of determining protein stability. Issue 10 (13th May 2020)

• Record Type: Journal Article
• Authors: Lindorff-Larsen, Kresten
• Is Part Of: Protein engineering, design & selection. Volume 32:Issue 10(2019)
• Page Start: 471
• Page End: 479
• Publication Date: 2020-05-13
• Subjects: Protein stability -- Statistics -- Denaturant; Protein engineering -- Periodicals; 660.63
• DOI: 10.1093/protein/gzaa010
• Languages: English
• ISSNs: 1741-0126

Abstract

Abstract: The linear extrapolation method to determine protein stability from denaturant-induced unfolding experiments is based on the observation that the free energy of unfolding is often a linear function of the denaturant concentration. The value in the absence of denaturant is then estimated by extrapolation from this linear relationship. Parameters and their confidence intervals are typically estimated by nonlinear least-squares regression. We have compared different methods for calculating confidence intervals and found that a simple method based on linear theory gives accurate results. We have also compared three different parameterizations of the linear extrapolation method and show that the most commonly used form is problematic since the stability and m -value are correlated in the nonlinear least-squares analysis. Parameter correlation can in some cases causes problems in the estimation of confidence intervals and regions and should be avoided when possible. Two alternative parameterizations show much less correlation between parameters.