Rigidity strengthening is a vital mechanism for protein-ligand binding

Protein-ligand binding is essential to almost all life processes. The understanding of protein-ligand interactions is fundamentally important to rational drug design and protein design. Based on large scale data sets, we show that protein rigidity strengthening or flexibility reduction is a pivoting mechanism in protein-ligand binding. Our approach based solely on rigidity is able to unveil a surprisingly long range contribution of four residue layers to protein-ligand binding, which has a ramification for drug and protein design. Additionally, the present work reveals that among various pairwise interactions, the short range ones within the distance of the van der Waals diameter are most important. It is found that the present approach outperforms all the other state-of-the-art scoring functions for protein-ligand binding affinity predictions of two benchmark data sets. Introduction Protein-ligand binding is fundamental to many biological processes in living organisms. The binding process involves detailed molecular recognition, synergistic protein-ligand corporation, and possible protein conformational change. Agonist binding alternates receptor function and trigger a physiological response, such as transmitter-mediated signal transduction, hormone and growth factor regulated metabolic pathways, and stimulus-initiated gene expression, enzyme production, and cell secretion, to name only a few. The understanding of protein-ligand interactions is essential for drug design and protein design, and has been a central issue in molecular biophysics, structural biology and medicine. A common belief is that protein-ligand binding is driven by free energy reduction, which is described in intermolecular forces, such as ionic bonds, hydrogen bonds, hydrophobic effects, and van der Waals (vdW) interactions.1,2 However, this view has not directly translated into accurate binding affinity predictions of large scale binding data sets, despite decades of efforts. Other potential mechanisms, such as flexibility reduction or rigidity enhancement, have been neglected in the current modeling and computation. Current understanding of flexibility with respect to protein-ligand binding is very limited. On the one hand, it is well-known that flexibility or plasticity of proteins as well as ligands facilitates the ligand docking during the binding process.3,4 On the other hand, protein-ligand binding reduces the system entropy, which favors the disassociation process. Since protein flexibility is intuitively associated with conformational entropy, binding induced flexibility reduction is widely regarded as unfavorable to the protein-ligand binding.5 This work offers evidence against this prevalent view. Thermodynamically, the protein-ligand binding process is described by the binding affinity, i.e., the change in the Gibbs free energy, which can be expressed in terms of enthalpy and entropy changes at a given temperature. The intricate interplay between enthalpy and entropy and over-simplified association between flexibility and entropy have made the role of flexibility in protein-ligand binding elusive. Fortunately, the availability of vast Address correspondences to Guo-Wei Wei. E-mail:[email protected]