Excision repair cross complementation group 1 (ERCC1) is an important protein in the nucleotide excision repair (NER) pathway, which is responsible for removing DNA adducts induced by platinum based compounds. The heterodimer ERCC1-XPF is one of two endonucleases required for NER. Genetic variations or polymorphisms in ERCC1 gene alter DNA repair capacity. Reduced DNA repair (NER) capacity may result in tumors and enhances cisplatin chemotherapy in cancer patients, which functions by causing DNA damage. Therefore, ERCC1 variants have the potential to be used as a strong candidate biomarker in cancer treatments. In this study we identified five variants V116M, R156Q, A199T, S267P, and R322C of ERCC1 gene as highly deleterious. Further structural and functional analysis has been conducted for ERCC1 protein in the presence of three variants V116M, R156Q, and A199T. Occurrence of theses variations adversely affected the regular interaction between ERCC1 and XPF protein. Analysis of 20 ns molecular dynamics simulation trajectories reveals that the predicted deleterious variants altered the ERCC1-XPF complex stability, flexibility, and surface area. Notably, the number of hydrogen bonds in ERCC1-XPF mutant complexes decreased in the molecular dynamic simulation periods. Overall, this study explores the link between the ERCC1 deleterious variants and cisplatin chemotherapy for various cancers with the help of molecular docking and molecular dynamic approaches. © 2013 Springer Science+Business Media.

George Priya Doss C

Department of Integrative Biology

School of Bio Sciences and Technology

Vellore Campus

Nagasundaram N.

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

Applied Biochemistry and Biotechnology

The DNA repair system is crucial to repair the error resulting in DNA replication. MSH2-MSH6 protein complex plays a significant role in maintaining the mismatch repair mechanism. Mutations in the interface between the two proteins compromise their function in the repair process. The present study aims to understand the impact of missense mutations in the interacting sites of the MSH2-MSH6 protein complex. MSH6 is unstable due to the disordered N-terminal domain. This is stabilized by the MSH2 hetero-dimerization. We used pathogenicity and stability predictors to identify the missense mutations that could be more pathogenic with the destabilizing property. The mutations W764C of MSH2, and L1201F and G1316E of MSH6 were predicted to be highly deleterious and destabilizing by all the in silico predictors. The dynamic motion of the native and mutant (W764C) MSH2-MSH6 protein complexes was further investigated using Molecular Dynamics Simulations of the GROMACS package. The Root Mean Square Deviation (RMSD), Radius of Gyration (Rg), and change in a number of intramolecular hydrogen bonds (H-bonds) were analyzed using the embedded packages of GROMACS. From the simulation studies, we observed higher deviation, lower protein compactness, and a decrease in the number of intramolecular hydrogen bonds in the mutant W764C MSH2-MSH6 protein complex. The observed results from the computational methods suggest the involvement of higher structural impact on the MSH2-MSH6 protein complex upon W764C mutation could affect the DNA repair mechanism. © 2019 Elsevier Inc.

DNA Repair Advances in Protein Chemistry and Structural Biology

Elucidating the role of interacting residues of the MSH2-MSH6 complex in DNA repair mechanism: A computational approach

An Integrated In Silico Approach for the Structural and Functional Exploration of Lipocalin 2 and its Functional Insights with Metalloproteinase 9 and Lipoprotein Receptor-Related Protein 2

Single amino acid substitutions (SAPs) belong to a class of SNPs in the coding region, which alter the protein function during the translation process. Storage of more information regarding SAPs in public databases will soon become a major hurdle in characterizing the functional SAPs. In such a demanding era, biology has to rely on bioinformatics, which can work its way through to solve the problems at hand by cutting huge amount of time and resources that are otherwise wasted. Here, we describe an overview of the existing repositories of variant databases and computational methods in predicting the effects of functional SAPs on protein stability, structure, function, drug response, and protein dynamics. This chapter will inspire many biologists with a greater promise in identifying the functional SAPs at the structural level, thereby understanding the molecular effects that are critical for personalized medicine diagnosis, prognosis, and treatment for diseases. © 2014 Elsevier Inc.

Advances in Protein Chemistry and Structural Biology

Computational Approaches and Resources in Single Amino Acid Substitutions Analysis Toward Clinical Research

Background: Distinguishing the deleterious from the massive number of non-functional nsSNPs that occur within a single genome is a considerable challenge in mutation research. In this approach, we have used the existing in silico methods to explore the mutation-structure-function relationship in the XPA gene. Materials and Methods: We used the Sorting Intolerant From Tolerant (SIFT), Polymorphism Phenotyping (PolyPhen), I-Mutant 2.0, and the Protein Analysis THrough Evolutionary Relationships methods to predict the effects of deleterious nsSNPs on protein function and evaluated the impact of mutation on protein stability by Molecular Dynamics simulations. Results: By comparing the scores of all the four in silico methods, nsSNP with an ID rs104894131 at position C108F was predicted to be highly deleterious. We extended our Molecular dynamics approach to gain insight into the impact of this non-synonymous polymorphism on structural changes that may affect the activity of the XPA gene. Conclusion: Based on the in silico methods score, potential energy, root-mean-square deviation, and root-mean-square fluctuation, we predict that deleterious nsSNP at position C108F would play a significant role in causing disease by the XPA gene. Our approach would present the application of in silico tools in understanding the functional variation from the perspective of structure, evolution, and phenotype. © 2011 NagaSundaram.

Journal of Carcinogenesis

Exploration of structural stability in deleterious nsSNPs of the XPA gene: A molecular dynamics approach

Single nucleotide polymorphism (SNP) serve as frequent genetic markers along the chromosome. They can, however, have important consequences for individual susceptibility to disease and reactions to medical treatment. Also, genetics of the human phenotype variation could be understood by knowing the functions of these SNPs. Currently, a vast literature exists reporting possible associations between SNPs and diseases. It is still a major challenge to identify the functional SNPs in a disease related gene. In this work, we have analyzed the genetic variation that can alter the expression and the function in chronic myeloid leukemia (CML) by ABL1 gene through computational methods. Out of the total 827 SNPs, 18 were found to be non-synonymous (nsSNPs). Among the 30 SNPs in the untranslated region, 3 SNPs were found in 5' and 27 SNPs were found in 3' untranslated regions (UTR). It was found that 16.7% nsSNPs were found to be damaging by both SIFT and PolyPhen server. UTR resource tool suggested that 6 out of 27 SNPs in the 3' UTR region were functionally significant. The two major mutations that occurred in the native protein (1OPL) coded by ABL1 gene were at positions 159 (L--&gt;P) and 178 (G--&gt;S). Val (6), Ala (7) and Trp (344) were found to be stabilizing residues in the native protein (1OPL) coded by ABL1 gene. Even though all the three residues were found in the mutant protein 178 (G--&gt;S), only two of them Val (6) and Ala (7) were acting as stabilizing residue in another mutant 159 (L--&gt;P). We propose from the overall results obtained in this work that, both the mutations 159 (L--&gt;P) and 178 (G--&gt;S) should be considered important in the chronic myeloid leukemia caused by ABL1 gene. Our results on this computational study will find good application with the cancer biologist working on experimental protocols.

Fulltext

Journal of Biomedical Informatics

Identification and structural comparison of deleterious mutations in nsSNPs of ABL1 gene in chronic myeloid leukemia: A bio-informatics study

Definitions

DNA Repair Endonuclease XPF

Pharmacogenomics

Association between DNA-repair polymorphisms and survival in pancreatic cancer patients treated with combination chemotherapy

PLoS ONE

In Silico and In Vitro Investigations of the Mutability of Disease-Causing Missense Mutation Sites in Spermine Synthase

Molecular Docking and Molecular Dynamics Study on the Effect of ERCC1 Deleterious Polymorphisms in ERCC1-XPF Heterodimer

Journal	Data powered by TypesetApplied Biochemistry and Biotechnology
Publisher	Data powered by TypesetSpringer Science and Business Media LLC
ISSN	0273-2289
Open Access	No