Defining scaffold geometries for interacting with proteins: geometrical classification of secondary structure linking regions

Abstract

Medicinal chemists synthesize arrays of molecules by attaching functional groups to scaffolds. There is evidence suggesting that some scaffolds yield biologically active molecules more than others, these are termed privileged substructures. One role of the scaffold is to present its side-chains for molecular recognition, and biologically relevant scaffolds may present side-chains in biologically relevant geometries or shapes. Since drug discovery is primarily focused on the discovery of compounds that bind to proteinaceous targets, we have been deciphering the scaffold shapes that are used for binding proteins as they reflect biologically relevant shapes. To decipher the scaffold architecture that is important for binding protein surfaces, we have analyzed the scaffold architecture of protein loops, which are defined in this context as continuous four residue segments of a protein chain that are not part of an α-helix or β-strand secondary structure. Loops are an important molecular recognition motif of proteins. We have found that 39 clusters reflect the scaffold architecture of 89% of the 23,331 loops in the dataset, with average intra-cluster and inter-cluster RMSD of 0.47 and 1.91, respectively. These protein loop scaffolds all have distinct shapes. We have used these 39 clusters that reflect the scaffold architecture of protein loops as biological descriptors. This involved generation of a small dataset of scaffold-based peptidomimetics. We found that peptidomimetic scaffolds with reported biological activities matched loop scaffold geometries and those peptidomimetic scaffolds with no reported biologically activities did not. This preliminary evidence suggests that organic scaffolds with tight matches to the preferred loop scaffolds of proteins, implies the likelihood of the scaffold to be biologically relevant.

Discovery and Characterization of a Potent Interleukin-6 Binding Peptide with Neutralizing Activity In Vivo

“…From the crystal structure of the hexameric IL-6/IL-6R/gp130 complex [ 16 ] the Cα-Cβ vectors of IL-6R residues that contact IL-6 were used to form a query. The Cα-atom is anchored to the backbone and the Cβ-atom is anchored to the first side-chain atom [ 17 , 18 ]. The Cα-Cβ vector of IL-6R residues that are in contact with IL-6 are a measure of the topology of the interaction surface.…”

Limiting Assumptions in the Design of Peptidomimetics

“…Because of their inherent rigidity due to multiple constraints, such small toxin proteins have been used as scaffolds to mimic relative sidechain orientations from known protein/protein interactions [Tran et al, ].…”

“…Based on concepts first implemented by the Bartlett group with CAVEAT [Lauri and Bartlett, ; Yang et al, ], the topological orientation of amino acid sidechains (CαCβ vectors) to characterize reverse turns was stressed by Tran et al [] rather that the classical definition by backbone torsional angles by Venkatachalam [], or the set of distances between backbone α‐carbons [Whitby et al, ]. The Tran classification scheme was used by Arbor and Marshall to characterize the ability of cyclic tetrapeptides (CTPs) to act as scaffolds for orientation of the four sidechains as seen in the diverse set of reverse turns found in the PDB [Arbor and Marshall, ].…”

What’s in a loop?

“…In addition, we probably need new ways to identify, describe and classify the highly dynamic, often disordered regions and arrangements of proteins, for example along the lines suggested by Peter Tompa [53] and others [54-56]. Accurate descriptions of loop structures may not be entirely trivial to obtain, but there are several algorithms and databases readily available to model loops in proteins [57-59].…”