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Computational and experimental approaches to reveal the effects of single nucleotide polymorphisms with respect to disease diagnostics.

ABSTRACT: DNA mutations are the cause of many human diseases and they are the reason for natural differences among individuals by affecting the structure, function, interactions, and other properties of DNA and expressed proteins. The ability to predict whether a given mutation is disease-causing or harmless is of great importance for the early detection of patients with a high risk of developing a particular disease and would pave the way for personalized medicine and diagnostics. Here we review existing methods and techniques to study and predict the effects of DNA mutations from three different perspectives: in silico, in vitro and in vivo. It is emphasized that the problem is complicated and successful detection of a pathogenic mutation frequently requires a combination of several methods and a knowledge of the biological phenomena associated with the corresponding macromolecules.

SUBMITTER: Kucukkal TG

PROVIDER: S-EPMC4100115 | biostudies-literature | 2014 May

REPOSITORIES: biostudies-literature

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Computational and experimental approaches to reveal the effects of single nucleotide polymorphisms with respect to disease diagnostics.

Kucukkal Tugba G TG Yang Ye Y Chapman Susan C SC Cao Weiguo W Alexov Emil E

International journal of molecular sciences 20140530 6

DNA mutations are the cause of many human diseases and they are the reason for natural differences among individuals by affecting the structure, function, interactions, and other properties of DNA and expressed proteins. The ability to predict whether a given mutation is disease-causing or harmless is of great importance for the early detection of patients with a high risk of developing a particular disease and would pave the way for personalized medicine and diagnostics. Here we review existing ...[more]

PMID: 24886813

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Project description:Dopamine receptor D4 (DRD4) plays a vital role in regulating various physiological functions, including attention, impulse control, and sleep, as well as being associated with various neurological diseases, including attention deficit hyperactivity disorder, novelty seeking, and so on. However, a comprehensive analysis of harmful nonsynonymous single nucleotide polymorphisms (nsSNPs) of the DRD4 gene and their effects remains unexplored. The aim of this study is to uncover novel damaging missense nsSNPs and their structural and functional effects on the DRD4 receptor. From the dbSNP database, we found 677 nsSNPs, and then we analyzed their functional consequences, disease associations, and effects on protein stability with fifteen in silico tools. Five variants, including L65ICL1P (rs1459150721), V1163.33D (rs761875546), I1293.46S (rs751467198), I1564.46T (rs757732258), and F2015.47S (rs199609858), were identified as the most deleterious mutations that were also present in the conserved region and showed lower interactions with neighboring residues. To comprehensively understand their impact, we docked agonist dopamine and antagonist nemonapride at the binding site of the receptor, followed by 200 ns molecular dynamics simulations. We identified the V116D and I129S mutations as the most damaging, followed by F201S in the dopamine-bound states. Both the V116D and I129S variants demonstrated significantly high RMSD, Rg, and SASA, and low thermodynamic stability. The F201S-dopamine complex exhibited lower compactness and higher motions, along with a significant loss of hydrogen bonds and active site interactions. By contrast, while interacting with nemonapride, the impact of the I156T and L65P mutations was highly deleterious; both showed lower stability, higher flexibility, and higher motions. Additionally, nemonapride significantly lost interactions with the active site, notably in the I156T variant. We also found the V116D-nemonapride complex as structurally damaging; however, the interaction patterns of nemonapride were less altered in the MMPBSA analysis. Overall, this study revealed five novel deleterious variants along with a comprehensive understanding of their effect in the presence of an agonist and antagonist, which could be helpful for understanding disease susceptibility, precision medicine, and developing potential drugs.

Dataset Information

Computational and experimental approaches to reveal the effects of single nucleotide polymorphisms with respect to disease diagnostics.

Publications

Computational and experimental approaches to reveal the effects of single nucleotide polymorphisms with respect to disease diagnostics.

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