Cecropin A–Magainin 2 (CA–MA) hybrid antimicrobial peptide (AMP), a combination of two naturally occurring AMPs, cecropin A and magainin 2 is preferred widely in biotechnological, nano and pharmaceutical applications. It exhibits a strong antibacterial activity with a characteristic reduced cytotoxic effect towards mammalian cells. In this study, three AMP structures native CA–MA hybrid and its tryptophan substitutes CA–MA L2 and CA–MA A2 was computationally studied to analyze their structural stability and functionality. Computational analysis like, intra-molecular interactions (25), relative stability (3.22) and instability index (−14.28) showed an increase in structural stability of native CA–MA hybrid. Additionally, the generated peptide ensembles showed a RMSD (3.98 Å), RMSF (0.202 Å), radius of gyration (11.98 Å), ovality (3.33) and hydrophobicity (69.7%) supporting native CA–MA along with hydrogen bond strength (−4.212 kcal/mol) and distribution comparatively. The distribution of secondary structure in native CA–MA hybrid showed the sequential maintenance of stable helical content along with helical stability (52.25%) and computed free energy (−1.74 kcal/mol) in membrane mimicking environment proving its functional activity comparatively. This study aids in designing stable AMP biodrugs with low cytotoxicity in future, the result can be potentially extended to other AMPs to assist in their exploitation as peptide and nano drugs. © 2017, Springer Science+Business Media New York.

Rajasekaran R

Department of Biotechnology

School of Bio Sciences and Technology

Vellore Campus

Senthilkumar B

Meshach Paul D

Srinivasan E

Vellore Institute of Technology (VIT) is a private university located in&nbsp;Tamil Nadu, India. Founded in 1984, as Vellore Engineering College, the institution offers 20 undergraduate, 34 postgraduate, four integrated and four research programs. It has campuses in Vellore, Amravati, Bhopal and Chennai.

VIT is one of the top ranked private universities in India according to NIRF, THE and QS Rankings.&nbsp;Govt. of India has recognized&nbsp;VIT, Vellore as an&nbsp;Institution of Eminence. This has allowed VIT to take independent quality initiatives and move up in world ranking.

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VIT University

Journal of Cluster Science

Schindler disease is a lysosomal storage disorder caused due to deficiency or defective activity of alpha-N-acetylgalactosaminidase (α-NAGA). Mutations in gene encoding α-NAGA cause wide range of diseases, characterized with mild to severe clinical features. Molecular effects of these mutations are yet to be explored in detail. Therefore, this study was focused on four missense mutations of α-NAGA namely, S160C, E325K, R329Q and R329W. Native and mutant structures of α-NAGA were analysed to determine geometrical deviations such as the contours of root mean square deviation, root mean square fluctuation, percentage of residues in allowed regions of Ramachandran plot and solvent accessible surface area, using conformational sampling technique. Additionally, global energy-minimized structures of native and mutants were further analysed to compute their intra-molecular interactions, hydrogen bond dilution and distribution of secondary structure. In addition, docking studies were also performed to determine variations in binding energies between native and mutants. The deleterious effects of mutants were evident due to variations in their active site residues pertaining to spatial conformation and flexibility, comparatively. Hence, variations exhibited by mutants, namely S160C, E325K, R329Q and R329W to that of native, consequently, lead to the detrimental effects causing Schindler disease. This study computationally explains the underlying reasons for the pathogenesis of the disease, thereby aiding future researchers in drug development and disease management. © 2016, International Association of Scientists in the Interdisciplinary Areas and Springer-Verlag Berlin Heidelberg.

Interdisciplinary Sciences: Computational Life Sciences

Exploration of Structural and Functional Variations Owing to Point Mutations in α-NAGA

Natowicz syndrome (mucopolysaccharidoses type 9) is a lysosomal storage disorder caused by deficient or defective human hyaluronidase 1. The disorder is not well studied at the molecular level. Therefore, a new in silico approach was proposed to study the molecular basis on which one clinically observed mutation, Glu268Lys, results in a defective enzyme. The native and mutant structures were subjected to comparative analyses using a conformational sampling approach for geometrical variables viz, RMSF, RMSD, and Ramachandran plot. In addition, the strength of a Cys207–Cys221 disulfide bond and electrostatic interaction between Arg265 and Asp206 were studied, as they are known to be involved in the catalytic activity of the enzyme. Native and mutant E268K showed statistically significant variations with p < 0.05 in RMSD, Ramachandran plot, strengths of disulfide bond, and electrostatic interactions. Further, single model analysis showed variations between native and mutant structures in terms of intra-protein interactions, hydrogen bond dilution, secondary structure, and dihedral angles. Docking analysis predicted the mutant to have a less favorable substrate binding energy compared to the native protein. Additionally, steered MD analysis indicated that the substrate should have more affinity to the native than mutant enzymes. The observed changes theoretically explain the less favorable binding energy of substrate towards mutant E268K, thereby providing a structural basis for its reduced catalytic activity. Hence, our study provides a basis for understanding the disruption in the molecular mechanism of human hyaluronidase 1 by mutation E268K, which may prove useful for the development of synthetic chaperones as a treatment option for Natowicz syndrome. © 2016, European Biophysical Societies' Association.

European Biophysics Journal

In silico approach to explore the disruption in the molecular mechanism of human hyaluronidase 1 by mutant E268K that directs Natowicz syndrome

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 intra-molecular 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 Å) 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. © 2016, Springer Science+Business Media New York.

International Journal of Peptide Research and Therapeutics

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

Tumor Biology

Impact of point mutation P29S in RAC1 on tumorigenesis

Discovery of peptides used in protein therapeutics proposes treatment for a wide range of infectious and chronic human diseases. Therapeutically significant peptides are developed from naturally occurring peptides or through de novo design. The characteristic features like small size, high stability and structural compatibility with target proteins identifies peptides as a potential class of drug and novel antibiotics. Recent acceptance of computer-aided drug design involving computational methods and resources for design and discovery of new therapeutic solutions has rapidly increased. This review describes systematic identification of the most imperative data sources and computational applications in designing peptides with desired biological features and enhanced therapeutic importance in pharmaceutical and nanomedicine firm. In addition, the current challenges for designing a stable peptide with favorable physiologic properties and the ways to overcome these issues are discussed with successful examples from literature. Using this approach, several peptides having anti-cancer, anti-angiogenic, anti-inflammatory and anti-microbial activities have been designed and biologically characterized. Copyright © 2016 American Scientific Publishers.

Journal	Data powered by TypesetJournal of Cluster Science
Publisher	Data powered by TypesetSpringer Science and Business Media LLC
ISSN	1040-7278
Open Access	No