title: Analysis of kinetics using a hybrid maximum-entropy/nonlinear-least-squares method: application to protein folding.
abstract: A hybrid analysis that combines the maximum entropy method (MEM) with nonlinear least squares (NLS) fitting has been developed to interpret a general time-dependent signal. Data that include processes of opposite sign and a slow baseline drift can be inverted to obtain both a continuous distribution of lifetimes and a sum of discrete exponentials. Fits by discrete exponentials are performed with initial parameters determined from the distribution of lifetimes obtained with the MEM. The regularization of the parameter space achieved by the MEM stabilizes the introduction of each successive exponential in the NLS fits. This hybrid approach is particularly useful when fitting by a large number of exponentials. Revision of the MEM "prior" based on features in the data can improve the lifetime distribution obtained. Standard errors in the mean are estimated automatically for raw data. The results presented for simulated data and for fluorescence measurements of protein folding illustrate the utility and accuracy of the hybrid algorithm. Analysis of the folding of dihydrofolate reductase reveals six kinetic processes, one more than previously reported.
authors.affiliation: Center for Molecular Modeling, Center for Information Technology, National Institutes of Health, Bethesda, Maryland 20892, USA. steinbac@helix.nih.gov
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Steinbach
authors.forename: Roxana
authors.initials: R
authors.lastname: Ionescu
authors.forename: C Robert
authors.initials: CR
authors.lastname: Matthews
mesh_terms: D000465:Algorithms; D001703:Biophysics / Q000379:methods*; D019277:Entropy; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007700:Kinetics; D016018:Least-Squares Analysis; D008727:Methotrexate / Q000494:pharmacology; D015233:Models, Statistical; D011485:Protein Binding; D017510:Protein Folding; D013050:Spectrometry, Fluorescence; D013762:Tetrahydrofolate Dehydrogenase / Q000737:chemistry*; D013997:Time Factors
chemical_list: D004791:Enzyme Inhibitors; D013762:Tetrahydrofolate Dehydrogenase; D008727:Methotrexate