Analysis of the Structural Stability Among Cyclotide Members Through Cystine Knot Fold that Underpins Its Potential Use as a Drug Scaffold

Recent emergence of plant derived peptide cyclotides, characterized with a cyclized head-to-tail backbone and three disulfide bonds forming cyclic cystine knot, has advanced the field of biopharmaceutics to next level. This conserved structural feature of cyclotides holds responsible for its outstanding resistance towards thermal, chemical and enzymatic degradation. Besides, the cyclotides are preferred widely in current research to develop them as potent peptide therapeutics, where the improvement of structural stability is a demanding task in pharmaceutical firm. Hence, in this work, the structural stability of six cyclotides of kalata family (kalata B1, kalata B2, kalata B5, kalata B7, kalata B8 and kalata B12) was investigated. Among all, maximum number of intramolecular interactions was observed only in kalata B1 (kB1). In addition, geometrical observables using conformational sampling of six kalata cyclotides also revealed that kB1 exhibited statistically significant structural stability in terms of contours of root mean square fluctuation, gyration radius, ovality and surface area (polar and non-polar). Furthermore, the distance of disulfide bridges (S-S within 2.2 angstrom) also confirmed that kB1 achieved maximum strength in terms of structural stability and accomplished remarkable functionality in terms of ovality as compared to other five kalata cyclotides. Accordingly, kB1 could be demonstrated as a stable template for the advancement of peptide therapeutics.