Gopalakrishnan T

Department of Database Systems

School of Computer Science and Engineering

Vellore Campus

Kalsi N

Jethi S

Purohit R.

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

Molecular and Cellular Biochemistry

Journal of Cellular Biochemistry

Investigation of structural stability and functionality of homodimeric gramicidin towards peptide‐based drug: a molecular simulation approach

Spinal muscular atrophy (SMA) is a neuromuscular disorder caused by the mutations in survival motor neuron 1 gene (SMN1). The molecular pathology of missense mutations in SMN1 is not thoroughly investigated so far. Therefore, we collected all missense mutations in the SMN1 protein, using all possible search terms, from three databases (PubMed, PMC and Google Scholar). All missense mutations were subjected to in silico pathogenicity, conservation, and stability analysis tools. We used statistical analysis as a QC measure for validating the specificity and accuracy of these tools. PolyPhen-2 demonstrated the highest specificity and accuracy. While PolyPhen-1 showed the highest sensitivity; overall, PolyPhen2 showed better measures in comparison to other in silico tools. Three mutations (D44V, Y272C, and Y277C) were identified as the most pathogenic and destabilizing. Further, we compared the physiochemical properties of the native and the mutant amino acids and observed loss of H-bonds and aromatic stacking upon the cysteine to tyrosine substitution, which led to the loss of aromatic rings and may reduce protein stability. The three mutations were further subjected to Molecular Dynamics Simulation (MDS) analysis using GROMACS to understand the structural changes. The Y272C and Y277C mutants exhibited maximum deviation pattern from the native protein as compared to D44V mutant. Further MDS analysis predicted changes in the stability that may have been contributed due to the loss of hydrogen bonds as observed in intramolecular hydrogen bond analysis and physiochemical analysis. A loss of function/structural impact was found to be severe in the case of Y272C and Y277C mutants in comparison to D44V mutation. Correlating the results from in silico predictions, physiochemical analysis, and MDS, we were able to observe a loss of stability in all the three mutants. This combinatorial approach could serve as a platform for variant interpretation and drug design for spinal muscular dystrophy resulting from missense mutations. © 2018, Springer Science+Business Media, LLC, part of Springer Nature.

Metabolic Brain Disease

Impact of missense mutations in survival motor neuron protein (SMN1) leading to Spinal Muscular Atrophy (SMA): A computational approach

The 14-3-3ζ protein acts as a molecular switch in regulating the TGF-β pathway, which alters from a tumor suppressor in the early stage of breast cancer to a promoter of metastasis in the late stage.

Molecular BioSystems

Expediting dynamics approach to understand the influence of 14-3-3ζ causing metastatic cancer through the interaction of YAP1 and β-TRCP

Rapid increase in antibiotic resistance has posed a worldwide threat, due to increased mortality, morbidity, and expenditure caused by antibiotic-resistant microbes. Recent development of the antimicrobial peptides like viscotoxin (Vt) has been successfully comprehended as a substitute for classical antibiotics. A structurally stable peptide, Vt can enhance antimicrobial property and can be used for various developmental purposes. Thus, structural stability among the antimicrobial peptides, Vt A1 (3C8P), A2 (1JMN), A3 (1ED0), B (1JMP), and C (1ORL) of Viscus album was computationally analyzed. In specific, the static confirmation of VtA3 showed high number of intramolecular interactions, along with an increase in hydrophobicity than others comparatively. Further, conformational sampling was used to analyze various geometrical parameters such as root mean square deviation, root mean square fluctuation, radius of gyration, and ovality which also revealed the structural stability of VtA3. Moreover, the statistically validated contours of surface area, lipophilicity, and distance constraints of disulfide bonds also supported the priority of VtA3 with respect to stability. Finally, the functional activity of peptides was accessed by computing their free energy of membrane association and membrane interactions, which defined VtA3 as functionally stable. Currently, peptide-based antibiotics and nanoparticles have attracted the pharmaceutical industries for their potential therapeutic applications. Thereby, it is proposed that viscotoxin A3 (1ED0) could be used as a preeminent template for scaffolding potentially efficient antimicrobial peptide-based drugs and nanomaterials in future.

Applied Biochemistry and Biotechnology

In Silico Template Selection of Short Antimicrobial Peptide Viscotoxin for Improving Its Antimicrobial Efficiency in Development of Potential Therapeutic Drugs

Cell Biochemistry and Biophysics

Biophysical Aspect of Huntingtin Protein During polyQ: An In Silico Insight

Fulltext

Journal of Biomolecular Structure and Dynamics

Role of ELA region in auto-activation of mutant KIT receptor: a molecular dynamics simulation insight

Drug resistance mechanism of PncA inMycobacterium tuberculosis

Amino Acids

In silico investigation of molecular mechanism of laminopathy caused by a point mutation (R482W) in lamin A/C protein

Studies on Adaptability of Binding Residues Flap Region of TMC-114 Resistance HIV-1 Protease Mutants

To understand the origin of the apparent low sensitivity to mutations exhibited by Darunavir, the binding energetics of this inhibitor to the HIV-1 protease was studied. Our research indicates that the observed effectiveness of Darunavir against the wild type HIV-1 protease is due to an extremely high affinity towards the wild-type and a relatively mild effect to the I50V and I54M mutations is due to low affinity towards the inhibitor. Good affinity of Darunavir accounts for the additive effects of well accommodation at binding site, good ligand-receptor electrostatic and van der waals energy while, the low susceptibility to I50V and I54M can be rationalized in terms of flexibility in the binding site residues that do not permit drug accommodation to the binding site distortions created by the mutation. The major flap mutations I50V and I54M lower the binding affinity of Darunavir by altering the position of binding site residues in 3D space. It decreases the electrostatic and van der waals interaction energy and further reduction in total receptor-ligand interaction energy. The results summarized in this paper emphasize the importance of shape complementarity and protein flexibility analysis of binding residual interactions in drug design. These data together with an interaction energy and flexibility analysis have established rigorous guidelines for the design of new and more powerful inhibitors. The principles learned from the HIV-1 protease can be applied to other design problems.

Interdisciplinary Sciences: Computational Life Sciences

Structural basis for the resilience of Darunavir (TMC114) resistance major flap mutations of HIV-1 protease

Computational investigation of molecular mechanism and neuropathological implications in Huntington disease

Journal	Data powered by TypesetMolecular and Cellular Biochemistry
Publisher	Data powered by TypesetSpringer Science and Business Media LLC
ISSN	0300-8177
Open Access	0