Topological side-chain classification of β-turns: Ideal motifs for peptidomimetic development

Abstract

Beta-turns are important topological motifs for biological recognition of proteins and peptides. Organic molecules that sample the side chain positions of beta-turns have shown broad binding capacity to multiple different receptors, for example benzodiazepines. Beta-turns have traditionally been classified into various types based on the backbone dihedral angles (phi2, psi2, phi3 and psi3). Indeed, 57-68% of beta-turns are currently classified into 8 different backbone families (Type I, Type II, Type I', Type II', Type VIII, Type VIa1, Type VIa2 and Type VIb and Type IV which represents unclassified beta-turns). Although this classification of beta-turns has been useful, the resulting beta-turn types are not ideal for the design of beta-turn mimetics as they do not reflect topological features of the recognition elements, the side chains. To overcome this, we have extracted beta-turns from a data set of non-homologous and high-resolution protein crystal structures. The side chain positions, as defined by C(alpha)-C(beta) vectors, of these turns have been clustered using the kth nearest neighbor clustering and filtered nearest centroid sorting algorithms. Nine clusters were obtained that cluster 90% of the data, and the average intra-cluster RMSD of the four C(alpha)-C(beta) vectors is 0.36. The nine clusters therefore represent the topology of the side chain scaffold architecture of the vast majority of beta-turns. The mean structures of the nine clusters are useful for the development of beta-turn mimetics and as biological descriptors for focusing combinatorial chemistry towards biologically relevant topological space.

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

“…One-to-one correspondence between a particular b-turn type and a particular cluster requires that the primary composition of a particular cluster to be of a particular b-turn type and the primary composition of the b-turn type to be of the particular cluster. We have previously argued that particular b-turn types can have more than one peak or mode structures and that members of different b-turn types can have similar side-chain shape [70]. Therefore, it was not unexpected that there was no one-to-one correspondence between b-turn types, which were classified based on the backbone dihedral angles and the clusters found here, which were classified based on the conformations of the side-chain.…”

c[D‐pro‐Pro‐D‐pro‐N‐methyl‐Ala] adopts a rigid conformation that serves as a scaffold to mimic reverse‐turns

“…37 The ability of our CTPs NMR conformation to mimic reverse turns was established by how well the NMR experimental structure had bonds overlapping the nine sets of four vectors established by Tran et al 37 as representative of reverse-turn Ca-Cb bonds. It was found that overlapping a Ca-Cb vector of a Tran et al cluster with a CÀ ÀH bond on a CTP gave an undesired biased overlap compared to overlapping a CÀ ÀC bond in the CTP.…”

“…It has been shown that reverse turns in the same classical-turn type can differ in the orientation of their side chains. 37 Because reverse turns are usually recognized in biological systems by their relative side-chain orientation and not direct interactions with their backbones, the classical classification method is not optimal. Recently, Tran et al 37 have elucidated nine classes of orientations of the four consecutive Ca-Cb bonds of a reverse turn that represent the vast majority (*90%) of reverse turns found in the PDB.…”

“…The DFT-minimized all trans conformer for c[pro-Propro-NMe-Ala] was tested for overlap with the nine reverseturn clusters of Tran et al 37 (Table III) Table III). This exemplifies the point of how well suited CTPs are at mimicking reverse turns.…”

Back to the future: Ribonuclease A

“…The distance between the C-alphas of Gly112 and Tyr115 and the distance between the carbonyl oxygen of Gly112 and amide hydrogen of Tyr115 were recorded ( Figure 14) at each time step after initial equilibration similar to the studies by Takeuchi and Marshall 126 on reverse-turn propensity. The virtual dihedral angle defined by the four C-alpha carbons of the reverse turn, as suggested by Tran et al, 127 of Gly112, Asn113, Pro114, and Tyr115 was also monitored as shown in Figure 14.…”