Investigating the Dynamics of Designed Ligand-Binding Proteins

Abstract

Protein design constitutes a challenging but promising area in biochemistry. Custom-designed ligand-binding proteins, in particular, present promising applications in small-molecule sensing, diagnostics, and in therapeutic scavenging of toxic compounds. Some of the challenges in designing ligand-binding proteins lie in the creation of a binding site that results in high affinity interaction but is also pre-organized and does not collapse in the absence of ligand. Here, we use molecular dynamics simulations to assess the cavity stability and binding affinity of designed proteins that have been tested experimentally. Our apo simulations provide information on the cavity pre-organization while holo simulations indicate protein-ligand affinity and correlate well with experimental observations. The results obtained can be used to guide further steps in protein design and to select appropriate metrics for the prediction of binding affinity of future un-tested proteins, aiding the protein design methodology.