Molecular Mechanisms of Disease-Causing Missense Mutations

Stefl, Shannon; Nishi, Hafumi; Petukh, Marharyta; Panchenko, Anna R.; Alexov, Emil

doi:10.1016/j.jmb.2013.07.014

Cited by 271 publications

(246 citation statements)

References 191 publications

(209 reference statements)

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“…(28)(29)(30)(31) We utilized the free energy perturbation (FEP) (32,33) method based on standard molecular dynamics sampling 6 and also several other methods that are known to be fast to obtain a consensus prediction. Below, the FEP method implementation in the current work is described along with other methods and webservers utilized.…”

Section: In Silico Modelingmentioning

confidence: 99%

Impact of Rett Syndrome Mutations on MeCP2 MBD Stability

et al. 2015

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Rett syndrome causing missense mutations in the methyl-CpG-binding domain (MBD) of methyl CpG-binding protein 2 (MeCP2) were investigated both in silico and in vitro to reveal their effect on protein stability. It is demonstrated that the vast majority of frequently occurring mutations in the human population indeed alter the MBD folding free energy by a fraction of a kcal/mol up to more than 1 kcal/mol. While the absolute magnitude of the change of the free energy is small, the effect on the MBD functionality may be substantial since the folding free energy of MBD is about 2 kcal/mol only. Thus, it is emphasized that the effect of mutations on protein integrity should be evaluated with respect to the wild-type folding free energy but not with the absolute value of the folding free energy change. Furthermore, it was observed that the magnitude of the effect is correlated neither with the burial of the mutation sites nor with the basic amino acid physicochemical property change. Mutations that strongly perturb the immediate structural features were found to have little effect on folding free energy, while very conservative mutations resulted in large changes of the MBD stability. This observation was attributed to the protein's ability to structurally relax and reorganize to reduce the effect of mutation. Comparison between in silico and in vitro results indicated that some Web servers perform relatively well, while the free energy perturbation approach frequently overpredicts the magnitude of the free energy change especially when a charged amino acid is involved.

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Section: In Silico Modelingmentioning

confidence: 99%

Impact of Rett Syndrome Mutations on MeCP2 MBD Stability

et al. 2015

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“…Many disease-causing nsSNPs may affect structure and stability of proteins, thereby altering or preventing their function (Dabhi & Mistry, 2014;Doss & NagaSundaram, 2012;Guo, Ning, Ren, Liu, & Yao, 2012). The magnitude of mutation's effect on protein stability can be quantified by changes in the folding free energy (ΔΔG) (Stefl et al, 2013). In this study, analysis of P5CR stability by the I-Mutant program reveals that the identified mutants have lower structural stability than the WT form.…”

Section: Discussionmentioning

confidence: 94%

“…It is well established that protein function is closely related to its stability (Stefl, Nishi, Petukh, Panchenko, & Alexov, 2013). Many disease-causing nsSNPs may affect structure and stability of proteins, thereby altering or preventing their function (Dabhi & Mistry, 2014;Doss & NagaSundaram, 2012;Guo, Ning, Ren, Liu, & Yao, 2012).…”

Section: Discussionmentioning

confidence: 99%

In silico screening, molecular docking, and molecular dynamics studies of SNP-derived human P5CR mutants

Sang

et al. 2016

Journal of Biomolecular Structure and Dynamics

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Pyrroline-5-carboxylate reductase (P5CR) encoded by PYCR1 gene is a housekeeping enzyme that catalyzes the reduction of P5C to proline using NAD(P)H as the cofactor. In this study, we used in silico approaches to examine the role of nonsynonymous single-nucleotide polymorphisms in the PYCR1 gene and their putative functions in the pathogenesis of Cutis Laxa. Among the 348 identified SNPs, 15 were predicted to be potentially damaging by both SIFT and PolyPhen tools; of them two SNP-derived mutations, R119G and G206W, have been previously reported to correlate with Cutis Laxa. These two mutations were therefore selected to be mapped to the wild-type (WT) P5CR structure for further structural and functional analyses. The results of comparative computational analyses using I-Mutant and Autodock reveal reductions in both stability and cofactor binding affinity of these two mutants. Comparative molecular dynamics (MD) simulations were performed to evaluate the changes in dynamic properties of P5CR upon mutations. The results reveal that the two mutations enhance the rigidity of P5CR structure, especially that of cofactor binding site, which could result in decreased kinetics of cofactor entrance and egress. Comparison between the structural properties of the WT and mutants during MD simulations shows that the enhanced rigidity of mutants results most likely from the increased number of inter-atomic interactions and the decreased number of dynamic hydrogen bonds. Our study provides novel insight into the deleterious effects of the R119G and G206W mutations on P5CR, and sheds light on the mechanisms by which these mutations mediate Cutis Laxa.

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“…[21]. It is to be expected that the significance for life science will increase because of their mutual influence on the conformational changes that may result in loss of specificity [22].…”

Section: The Pressure (Gpa) As a Function Of The Lattice Parameter(a)mentioning

confidence: 99%

A Molecular Description of Superconductivity of Sulfur Hydride and Related Systems under High-Pressure Conditions

Buck¹

2017

OJPC

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It has been shown that the recently discovered sulfur trihydride (H 3 S) can be considered as a superconductor with a transition temperature Tc of 203 Kelvin (K) at 155 GigaPascals (GPa). This is the highest Tc value reported for any superconductor. The established superconductivity occurs via the formation of a molecular system with sulfur atoms arranged on a body-centered cubic lattice. It has been generally accepted that the high Tc value is the result of an efficient electron-phonon interaction. The responsible substance formed by H 2 S under high pressure, may be considered as a compound with H 3 S stoichiometry creating an impressive network with hydrogens. We will focus on the hydrogen bonding between sulfur and hydrogens demonstrating a symmetrical arrangement. The geometry of the individual radical compound in relation to corresponding systems will be discussed. Ab initio calculations based on a linear three-center two-, three-and four-electron type of bonding clearly visualized in combination with the dynamics of the Van't Hoff concept, as described by us in various papers, give a good description of this exclusive network. We also discuss the superconductivity of related phosphorus hydrides and focus on the stability and geometrical differences with respect to the H 3 S system. These differences are significant, demonstrating the diversity in various structures in showing superconductivity.

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Molecular Mechanisms of Disease-Causing Missense Mutations

Cited by 271 publications

References 191 publications

Impact of Rett Syndrome Mutations on MeCP2 MBD Stability

Impact of Rett Syndrome Mutations on MeCP2 MBD Stability

In silico screening, molecular docking, and molecular dynamics studies of SNP-derived human P5CR mutants

A Molecular Description of Superconductivity of Sulfur Hydride and Related Systems under High-Pressure Conditions

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