SAAFEC: Predicting the Effect of Single Point Mutations on Protein Folding Free Energy Using a Knowledge-Modified MM/PBSA Approach

Getov, Ivan; Petukh, Marharyta; Alexov, Emil

doi:10.3390/ijms17040512

Cited by 79 publications

(67 citation statements)

References 41 publications

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“…The binding free energy changes upon missense mutations (ΔΔΔ G ) were predicted with webservers including BeAtMuSiC, MutaBind, and SAAMBE . The folding free energy changes upon missense mutations (ΔΔ G ) were evaluated with mCSM, SDM, DUET, and SAAFEC servers.…”

Section: Methodsmentioning

confidence: 99%

Cofactors-loaded quaternary structure of lysine-specific demethylase 5C (KDM5C) protein: Computational model

Peng

Alexov

2016

Proteins

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The KDM5C gene (also known as JARID1C and SMCX) is located on the X chromosome and encodes a ubiquitously expressed 1,560-aa protein, which plays an important role in lysine methylation (specifically reverses tri- and di-methylation of Lys4 of histone H3). Currently, thirteen missense mutations in KDM5C have been linked to X-linked mental retardation. However, the molecular mechanism of disease is currently unknown due to the experimental difficulties in expressing such large protein and the lack of experimental 3D structure. In this work, we utilize homology modeling, docking, and experimental data to predict 3D structures of KDM5C domains and their mutual arrangement. The resulting quaternary structure includes KDM5C JmjN, ARID, PHD1, JmjC, ZF domains, substrate histone peptide, enzymatic cofactors and DNA. The predicted quaternary structure was investigated with molecular dynamic simulation for its stability, and further analysis was carried out to identify features measured experimentally. The predicted structure of KDM5C was used to investigate the effects of disease-causing mutations and it was shown that the mutations alter domain stability and inter-domain interactions. The structural model reported in this work could prompt experimental investigations of KDM5C domain-domain interaction and exploration of undiscovered functionalities.

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Section: Methodsmentioning

confidence: 99%

Cofactors-loaded quaternary structure of lysine-specific demethylase 5C (KDM5C) protein: Computational model

Peng

Alexov

2016

Proteins

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“…Traditionally, most of computational methods analyze an absolute or relative free energy changes (ΔΔG) with a purpose to evaluate the effect of mutation in a single amino acid181920212223. Typically, ΔΔG values have a wide range from negative values (stabilizing mutations) to higher positive values (destabilizing mutations).…”

Section: Discussionmentioning

confidence: 99%

“…Several tools, including the SNPeffect database, are able to predict the functional consequences of missense mutations in protein structures181920212223. Many of these methods depend on evolutionary sequence conservation.…”

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confidence: 99%

In silico Mapping of Protein Unfolding Mutations for Inherited Disease

McCafferty

Sergeev

2016

Sci Rep

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The effect of disease-causing missense mutations on protein folding is difficult to evaluate. To understand this relationship, we developed the unfolding mutation screen (UMS) for in silico evaluation of the severity of genetic perturbations at the atomic level of protein structure. The program takes into account the protein-unfolding curve and generates propensities using calculated free energy changes for every possible missense mutation at once. These results are presented in a series of unfolding heat maps and a colored protein 3D structure to show the residues critical to the protein folding and are available for quick reference. UMS was tested with 16 crystal structures to evaluate the unfolding for 1391 mutations from the ProTherm database. Our results showed that the computational accuracy of the unfolding calculations was similar to the accuracy of previously published free energy changes but provided a better scale. Our residue identity control helps to improve protein homology models. The unfolding predictions for proteins involved in age-related macular degeneration, retinitis pigmentosa, and Leber’s congenital amaurosis matched well with data from previous studies. These results suggest that UMS could be a useful tool in the analysis of genotype-to-phenotype associations and next-generation sequencing data for inherited diseases.

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“…Furthermore, various methods, software, and webservers were developed utilizing DelPhi. These resources include changes of folding (SAAMBE method) and binding (SAAFEC and SAMPDI) free energies due to mutations, predicting nonspecifically bound ions (BION method), DelPhiPKa method and webservers for predicting pKa's in proteins, RNAs and DNAs, and calculating the electrostatic forces between macromolecules (DelPhiForce) …”

Section: Introductionmentioning

confidence: 99%

DelPhi Suite: New Developments and Review of Functionalities

Jia

Chakravorty

et al. 2019

J Comput Chem

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Electrostatic potential, energies, and forces affect virtually any process in molecular biology, however, computing these quantities is a difficult task due to irregularly shaped macromolecules and the presence of water. Here, we report a new edition of the popular software package DelPhi along with describing its functionalities. The new DelPhi is a C++ object‐oriented package supporting various levels of multiprocessing and memory distribution. It is demonstrated that multiprocessing results in significant improvement of computational time. Furthermore, for computations requiring large grid size (large macromolecular assemblages), the approach of memory distribution is shown to reduce the requirement of RAM and thus permitting large‐scale modeling to be done on Linux clusters with moderate architecture. The new release comes with new features, whose functionalities and applications are described as well. © 2019 The Authors. Journal of Computational Chemistry published by Wiley Periodicals, Inc.

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SAAFEC: Predicting the Effect of Single Point Mutations on Protein Folding Free Energy Using a Knowledge-Modified MM/PBSA Approach

Cited by 79 publications

References 41 publications

Cofactors-loaded quaternary structure of lysine-specific demethylase 5C (KDM5C) protein: Computational model

Cofactors-loaded quaternary structure of lysine-specific demethylase 5C (KDM5C) protein: Computational model

In silico Mapping of Protein Unfolding Mutations for Inherited Disease

DelPhi Suite: New Developments and Review of Functionalities

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