Hot Spots and Transient Pockets: Predicting the Determinants of Small-Molecule Binding to a Protein–Protein Interface

Abstract

Protein-protein interfaces are considered difficult targets for small-molecule protein-protein interaction modulators (PPIMs ). Here, we present for the first time a computational strategy that simultaneously considers aspects of energetics and plasticity in the context of PPIM binding to a protein interface. The strategy aims at identifying the determinants of small-molecule binding, hot spots, and transient pockets, in a protein-protein interface in order to make use of this knowledge for predicting binding modes of and ranking PPIMs with respect to their affinity. When applied to interleukin-2 (IL-2), the computationally inexpensive constrained geometric simulation method FRODA outperforms molecular dynamics simulations in sampling hydrophobic transient pockets. We introduce the PPIAnalyzer approach for identifying transient pockets on the basis of geometrical criteria only. A sequence of docking to identified transient pockets, starting structure selection based on hot spot information, RMSD clustering and intermolecular docking energies, and MM-PBSA calculations allows one to enrich IL-2 PPIMs from a set of decoys and to discriminate between subgroups of IL-2 PPIMs with low and high affinity. Our strategy will be applicable in a prospective manner where nothing else than a protein-protein complex structure is known; hence, it can well be the first step in a structure-based endeavor to identify PPIMs.

Protein–protein interactions between SWCNT/chitosan/EGF and EGF receptor: a model of drug delivery system

“…In this work, per-residue decomposition analysis was performed by the MM-GBSA module in the AMBER 10 (Gohlke, et al, 2003;Metz et al, 2012). In contrast to alanine scanning method, the per-residue decomposition analysis, based on Golkhe and coworkers approach (Gohlke, et al, 2003), is a non-perturbing alternative method which estimates the contribution of each residue to the binding energy by means of component analysis.…”

Modulating Protein-Protein Interactions: From Structural Determinants of Binding to Druggability Prediction to Application

“…Accordingly, binding pocket detection algorithms have been developed that can be sub-divided into two major classes [36], geometry-based [115][116][117][118][119][120][121][122] and energy-based ones [123][124][125][126][127][128][129][130]. Methods using structure and sequence comparison [131][132][133][134][135] or techniques taking into account the dynamics of protein structures [34,35,107,[136][137][138][139] have been reported less frequently. Several authors reviewed the available methods [36,107,112,140], especially those applied to the identification of proteinligand binding sites in classical targets.…”

“…First, proteins are marginally stable molecules [33] forming an ensemble of conformational states, each of which could potentially interact with a binding partner [31]. These conformational changes can result in the formation of cavities in the interfaces that could not be detected by visual inspection of the static representation of a crystal structure [34,35]. That way, proteins can exhibit grooves that allow for molecular recognition and binding [36].…”

Pocket-Based Drug Design: Exploring Pocket Space

“…Intuitively, pockets are surface concavities of proteins where a substrate might bind, whereas the concept of "druggable" pockets refers to target proteins where small drug-like molecules have been shown to bind (6)(7)(8)(9)(10). Other descriptions/definitions of binding pockets include novel binding site centric chemical space (4), the establishment of relationships across different target class (11), static pockets, transient pockets, dynamic pockets (12,13), monomeric pockets, as well as multimeric interfacial pockets (14)(15)(16). In summary, our categorization, description, and understanding of binding pockets is quickly evolving and is paving the way to the development of novel therapeutics and improved treatment of human disease.…”