Specific noncovalent interactions that are indicative of attractive, directional intermolecular forces have always been of key interest to medicinal chemists in their search for the “glue” that holds drugs and their targets together. With the rapid increase in the number of solved biomolecular structures as well as the performance enhancement of computer hardware and software in recent years, it is now possible to give more comprehensive insight into the geometrical characteristics and energetic landscape of certain sophisticated noncovalent interactions present at the binding interface of protein receptors and small ligands based on accumulated knowledge gaining from the combination of two quite disparate but complementary approaches: crystallographic data analysis and quantum-mechanical ab initio calculation. In this perspective, we survey massive body of published works relating to structural characterization and theoretical investigation of three kinds of strong, specific, direct, enthalpy-driven intermolecular forces, including hydrogen bond, halogen bond and salt bridge, involved in the formation of protein-ligand complex architecture in order to characterize their biological functions in conferring affinity and specificity for ligand recognition by host protein. In particular, the biomedical implications of raised knowledge are discussed with respect to potential applications in rational drug design.

The recent focus on protein-protein interaction networks has increasingly been shifted towards the disruption of protein complexes, which either are mediated by the binding of a globular domain in one protein to a short peptide stretch in another, or involve flat, large, and hydrophobic interfaces that classical small-molecule agents are not always ideally suited. Rational design of therapeutic peptides with high affinity targeting such interactions has emerged as a new and promising tool in discovery of potential drug candidates against associated diseases. The design is commonly based on bioinformatics methods or molecular modeling techniques, indirectly exploiting structure-activity relationship at the level of peptide sequence or directly deriving lead entities from protein complex architecture. Here, a newly rising subfield called computational peptidology that focuses on the use of computational and theoretical approaches to treat peptiderelated problems is comprehensively reviewed on the design and discovery of peptide agents targeting protein-protein interactions. We address a systematic discussion on several representative cases in which the computational peptidology is successfully employed to develop peptide therapeutics. Besides, some problems and pitfalls accompanied with the current use of computational methods in peptide modeling and design are also present.

Self-binding peptides (SBPs) represent a novel biomolecular phenomenon spanning between folding and binding, where a short peptide segment within a monomeric protein fulfills biological functions by dynamically binding to/unbinding from its target domain in the same monomer. Here, we were able to quantitatively reconstruct the complete structural dynamics picture of binding of free SBPs to their target domains for five representative SBP systems by carrying out the state-of-the-art molecular dynamics (MD) simulations. In the picture, a two-step binding mechanism for SBP–domain recognition and association was proposed, which includes a fast, nonspecific diffusive phase and a slow, specific organizational phase. The electrostatic interactions and desolvation effects play a predominant role in the first phase that leads to the formation of a metastable encounter complex, while conformational rearrangement is observed in the second phase to optimize the exquisite network of nonbonded chemical forces such as hydrogen bonds and salt bridges across the complex interface. From an energetic point of view, a funnel-shape enthalpy landscape steers these SBPs towards their native bound state and thus facilitates the binding process. However, the binding exhibits typical enthalpy–entropy compensation due to the high flexibility of peptides that results in a relatively low affinity for SBP–domain binding and forces the SBP systems to rapidly switch between the bound and unbound states. In addition, slight conformational changes in the target domain and/or in the polypeptide linker between the domain and peptide can significantly affect the energetic properties and dynamic behavior of the fine-tuned binding process of SBP–domain recognition.