LIGAND-BINDING TO PROTEINS - THE BINDING LANDSCAPE MODEL

Models of ligand binding are often based on four assumptions: (1) ster ic fit: that binding is determined mainly by shape complementarity; (2 ) native binding: that ligands mainly bind to native states; (3) local ity: that ligands perturb protein structures mainly at the binding sit e; and (4) continuity: that small changes in ligand or protein structu re lead to small changes in binding affinity. Using a generalization o f the 2D HP lattice model, we study ligand binding and explore these a ssumptions. We first validate the model by showing that it reproduces typical binding behaviors. We observe ligand-induced denaturation, ANS and heme-like binding, and ''lock-and-key'' and ''induced-fit'' speci fic binding behaviors characterized by Michaelis-Menten or more cooper ative types of binding isotherms. We then explore cases where the mode l predicts violations of the standard assumptions. For example, very d ifferent binding modes can result from two ligands of identical shape. Ligands can sometimes bind highly denatured states more tightly than native states and yet have Michaelis-Menten isotherms. Even low-popula tion binding to denatured states can cause changes in global stability , hydrogen-exchange rates, and thermal B-factors, contrary to expectat ions, but in agreement with experiments. We conclude that ligand bindi ng, similar to protein folding, may be better described in terms of en ergy landscapes than in terms of simpler mass-action models.