A Multiscale Model for Quantitative Prediction of Insulin Aggregation Nucleation Kinetics

Abstract

We combined kinetic, thermodynamic, and structural information from single molecule (protein folding) and two molecule (association) explicit-solvent simulations for determination of kinetic parameters in protein aggregation nucleation with insulin as model protein. A structural bioinformatics approach was developed to account for heterogeneity of aggregation-prone species with the transition complex theory found applicable in modeling association kinetics involving non-native species. We show that a key simplification arises from presence of only a few relevant modes for non-native association kinetics. The kinetic parameters thus obtained were used in a population balance model and accurate predictions for aggregation nucleation time varying over two orders of magnitude with changes in concentration of insulin or an aggregation-inhibitor ligand were obtained while an empirical parameter set was not found to be transferable for prediction of ligand effects. This physically determined kinetic parameter set also allowed identification of the rate-limiting step in aggregation nucleation. TOC Graphic O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/431119v1_ufig1.gif" ALT="Figure 1"> View larger version (28K): org.highwire.dtl.DTLVardef@7ff3e4org.highwire.dtl.DTLVardef@653c90org.highwire.dtl.DTLVardef@6b4675org.highwire.dtl.DTLVardef@deab8a_HPS_FORMAT_FIGEXP M_FIG C_FIG