Recent developments in high-throughput discovery and genotyping have generated a tremendous amount of information about the existence of single amino acid polymorphisms (SAPs). Detailed understanding of the SAPs that affect protein structure and function can provide us valuable insight into disease genotype-phenotype correlations. Functional variants of biological importance are likely to be missed in large-scale analysis. Over the past decade, numerous efforts are underway in understanding and characterizing the potential consequences of variants in assessing the risk associated with vitelliform macular dystrophy (VMD). Yet, in spite of this success, we conducted a first SAP analysis via evolutionary-based in silico pipeline to unravel functional SAPs from a pool, containing both functional and neutral ones. Furthermore, based on the prediction scores, a ranking system was developed to prioritize the functional SAPs in order to minimize the number of SAPs screened for further genotyping. © 2014 Elsevier Inc.

George Priya Doss C

Department of Integrative Biology

School of Bio Sciences and Technology

Vellore Campus

Chakraborty C

Monford Paul Abishek N

Kumar D

Narayanan V.

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

Application of evolutionary based in silico methods to predict the impact of single amino acid substitutions in vitelliform macular dystrophy.

Advances in Protein Chemistry and Structural Biology

Recent statistics describe breast cancer as the leading cause of death among women across the world with varied causes and reasons. Lifestyle, diet, genetic and environmental factors introduce their generous contributions towards breast cancer, among which genetic factors have lately become one of the most important aspects in understanding the mechanism. Although various genes have already been reported in causing breast cancer, PIK3CA stands second on the list. Mutations observed in this gene have the ability to trigger the different activities of the cell, thereby bypassing the regular cellular cycle. Among the mutations in PIK3CA, three hotspot mutations were commonly reported, one in the catalytic domain (position HIS1047) and other two in the helical domain (position GLU542 and GLU545). In the helical domain of PIK3CA, the lysine substitution at 542–545 positions was significantly studied in causing breast cancer. To compare the deleterious effect of these mutations, in silico prediction tools along with molecular dynamics simulations and molecular docking approach was initiated to analyse the change in binding landscape upon mutation. In this comparative analysis, we report that the mere existence of mutant E545K can trigger the function of the protein but may not be as harmful as H1047R. Among the two mutations E542K and E545K, the latter shows the most deleterious effect that correlates with the previous reported experimental studies. We assume the results observed in this combinatorial computational study might further pave a better way for providing better treatment procedures. © 2016 Informa UK Limited, trading as Taylor &amp; Francis Group.

Journal of Biomolecular Structure and Dynamics

Role of E542 and E545 missense mutations of PIK3CA in breast cancer: a comparative computational approach

Mutations in the fibrinogen gamma chain (FGG) gene have been associated with various disorders, such as dysfibrinogenemia, thrombophilia, and hypofibrinogenemia. A literature survey showed that a residue exchange in fibrinogen Milano I from γ Asp to Val at position 330 impairs fibrin polymerization. The D356V (D330V) mutation located in the C-terminus was predicted to be highly deleterious and to affect the function of the protein. The pathogenicity of the altered gene and changes in protein functions were predicted using in silico methods, such as SIFT, PolyPhen 2, I-Mutant 3.0, Align GV-GD, PhD-SNP, and SNPs&amp;GO. The secondary structure of the mutant protein was unwound by the end of the 50-ns simulation period, and a structural change in the helix-turn transition of the alpha-helical (352-356) region residues was observed. Moreover, a change in the length of the helical region was visualized in the mutant trajectory file, indicating the local transient unfolding of the protein. The obtained computational results suggest that the substitution of the neutral amino acid valine for the acidic amino acid aspartic acid at position 356 results in an unwound conformation within 50 ns, which might contribute to defective polymerization. Our analysis also provides insights into the effect of the conformational change in the D356V (D330V) mutant on protein structure and function.

Molecular dynamics-based analyses of the structural instability and secondary structure of the fibrinogen gamma chain protein with the D356V mutation

Myelin protein zero (MPZ) gene encodes MPZ protein is a vital component of the myelin sheath. Mutationsassociated with MPZ gene leads to severe de-hypomyelination Dejerine-Sottas syndrome type B (DSSB) also termed as Charcot-Marie-Tooth disease (CMT) type 3. In this work, we employed a set of various in silico prediction methods to screen 97 nsSNPs associated with MPZ gene. Based on this, we identified the nsSNPs to be most deleterious and pathogenic associated with DSSB. To get more insight into the mutational effect at three-dimensional structural level, we modeled the homology structure of native type as well as I30T and I30M mutant of MPZ protein using Modeler 9.13 software. Molecular dynamics simulation was initiated to explain the impact of the mutation on its structure and function. The obtained results depict that the protein with I30T mutation had variable structural conformation and dynamic behavior than native and mutant I30M of MPZ protein. We hope our computational insight might be helpful in rationalizing the deleterious mutations in DSSB and the advancement of novel pharmacological strategy.

Journal of Theoretical Biology

Impact of I30T and I30M substitution in MPZ gene associated with Dejerine–Sottas syndrome type B (DSSB): A molecular modeling and dynamics

O6 -methylguanine-DNA methyltransferase (MGMT) is one of the major DNA repair protein that counteracts the alkalyting agent-induced DNA damage by replacing O6 -methylguanine (mutagenic lesion) back to guanine, eventually suppressing the mismatch errors and double strand crosslinks. Exonic alterations in the form of nucleotide polymorphism may result in altered protein structure that in turn can lead to the loss of function. In the present study, we focused on the population feared for high exposure to alkylating agents owing to their typical and specialized dietary habits. To this end, gastric cancer patients pooled out from the population were selected for the mutational screening of a specific error prone region of MGMT gene. We found that nearly 40% of the studied neoplastic samples harbored missense mutation at codon151 resulting into Serine to Isoleucine variation. This variation resulted in bringing about the structural disorder, subsequently ensuing into a major stoichiometric variance in recognition domain, substrate binding and selectivity loop of the active site of the MGMT protein, as observed under virtual microscope of molecular dynamics simulation (MDS). The atomic insight into MGMT protein by computational approach showed a significant change in the intra molecular hydrogen bond pattern, thus leading to the observed structural anomalies. To further examine the mutational implications on regulatory plugs of MGMT that holds the protein in a DNA-Binding position, a MDS based analysis was carried out on, all known physically interacting amino acids essentially clustered into groups based on their position and function. The results generated by physical-functional clustering of protein indicated that the identified mutation in the vicinity of the active site of MGMT protein causes the local and global destabilization of a protein by either eliminating the stabilizing salt bridges in cluster C3, C4, and C5 or by locally destabilizing the "protein stabilizing hing" mapped on C3-C4 cluster, preceding the active site. © 2015 Chikan et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Fulltext

PLOS ONE

Atomic Insight into the Altered O6-Methylguanine-DNA Methyltransferase Protein Architecture in Gastric Cancer

Definitions

Adult-onset foveomacular vitelliform dystrophy

The Scientific World Journal

Prediction of Deleterious Nonsynonymous Single-Nucleotide Polymorphism for Human Diseases

Nucleic Acids Research

Exploring functional variant discovery in non-coding regions with SInBaD

PANTHER in 2013: modeling the evolution of gene function, and other gene attributes, in the context of phylogenetic trees

PLoS ONE

Relating the Disease Mutation Spectrum to the Evolution of the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR)

Application of Evolutionary Based in Silico Methods to Predict the Impact of Single Amino Acid Substitutions in Vitelliform Macular Dystrophy

Journal	Data powered by TypesetAdvances in Protein Chemistry and Structural Biology
Publisher	Data powered by TypesetElsevier
ISSN	1876-1623
Open Access	No