Predicting Changes in the Stability of Proteins and Protein Complexes: A Study of More Than 1000 Mutations

Guérois, Raphaël; Nielsen, Jens Erik; Serrano, Luís

doi:10.1016/s0022-2836(02)00442-4

Cited by 1,619 publications

(1,878 citation statements)

References 90 publications

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“…In order to identify the interacting region of two peptides studied in this work (DEEFLIKIAAIDN from human phosphatidylinositol 4-kinase and FTVYGLLDKAQDLF from human melanotransferrin), the peptides were divided into nine amino acids length fragments. Using the FoldX [43][44][45] software, the core positions of the CLIP peptide were mutated to reproduce every one of these nine amino acid sequences. FoldX generated 10 different models considering different putative residues rotamers for each of the nine amino acid sequence.…”

Section: Modeling Of Hla-dr8 With Peptidementioning

confidence: 99%

The peptide-binding motif of HLA-DR8 shares important structural features with other type 1 diabetes-associated alleles

et al. 2011

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The objective of this study was to characterize the peptide-binding motif of the major histocompatibility complex (MHC) class II HLA-DR8 molecule included in the type 1 diabetes-associated haplotype DRB1*0801-DQA1*0401/DQB1*0402 (DR8-DQ4), and compare it with that of other diabetes-associated MHC class II alleles; DR8-bound peptides were eluted from an HLA-DR homozygous lymphoblastoid cell line. The repertoire was characterized by peptide sequencing using a LTQ ion trap mass spectrometer coupled to a multidimensional liquid chromatography system. After validation of the spectra identification, the definition of the HLA-DR8 peptide-binding motif was achieved from the analysis of 486 natural ligands, based on serial alignments of all possible HLA-DR-binding cores. The DR8 motif showed a strong similarity with the peptide-binding motifs of other MHC class II diabetes-associated alleles, HLA-DQ8 and H-2 I-A g7 . Similar to HLA-DQ8 and H-2 I-A g7 , HLA-DR8 preferentially binds peptides with an acidic residue at position P9 of the binding core, indicating that DR8 is the susceptibility component of the DR8-DQ4 haplotype. Indeed, some DR8 peptides were identical to peptides previously identified as DQ8-or I-A g7 ligands, and several diabetes-specific peptides associated with DQ8 or I-A g7 could theoretically bind to HLA-DR8. These data further strengthen the association of HLA-DR8 with type I diabetes.

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Section: Modeling Of Hla-dr8 With Peptidementioning

confidence: 99%

The peptide-binding motif of HLA-DR8 shares important structural features with other type 1 diabetes-associated alleles

et al. 2011

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“…25 The influence of the residues on the structural stability was studied by computational alanine scanning using the Foldx4 software. 26 The structural stability of the wild-type protein was computed and compared with that of the alanine mutants. The stability is estimated as a difference between the free energy of the unfolded and folded states of the protein.…”

Section: Molecular Modeling Analysismentioning

confidence: 99%

Biallelic variants in LINGO1 are associated with autosomal recessive intellectual disability, microcephaly, speech and motor delay

Ansar

Riazuddin

Sarwar

et al. 2018

Genetics in Medicine

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Purpose: To elucidate the novel molecular cause in two unrelated consanguineous families with autosomal recessive intellectual disability.Methods: A combination of homozygosity mapping and exome sequencing was used to locate the plausible genetic defect in family F162, while only exome sequencing was followed in the family PKMR65. The protein 3D structure was visualized with the University of California-San Francisco Chimera software.Results: All five patients from both families presented with severe intellectual disability, aggressive behavior, and speech and motor delay. Four of the five patients had microcephaly. We identified homozygous missense variants in LINGO1, p.(Arg290His) in family F162 and p.(Tyr288Cys) in family PKMR65. Both variants were predicted to be pathogenic, and segregated with the phenotype in the respective families. Molecular modeling of LINGO1 suggests that both variants interfere with the glycosylation of the protein.Conclusion: LINGO1 is a transmembrane receptor, predominantly found in the central nervous system. Published loss-offunction studies in mouse and zebrafish have established a crucial role of LINGO1 in normal neuronal development and central nervous system myelination by negatively regulating oligodendrocyte differentiation and neuronal survival. Taken together, our results indicate that biallelic LINGO1 missense variants cause autosomal recessive intellectual disability in humans.

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“…Guerois et al [104] developed the FOLD-X energy function to study the stabilities of 1088 mutants. They used a comprehensive set of parameters to describe the van der Waals, solvation, hydrogen-bonding, electrostatic and entropic contribution to the protein stability, and obtained a correlation of 0.64 for the blind test set after training their parameters on 339 mutants [104]. Khatun et al [105] utilized contact potentials to predict ΔΔG of three sets of 303, 658 and 1356 mutants and their prediction correlations varied between 0.45 to 0.78.…”

Section: Protein Stabilitymentioning

confidence: 99%

“…To our knowledge, protein dynamics and flexibility have not been explicitly modeled in previous methods. Ignoring protein flexibility prohibits the application of current prediction methods to a wide range of mutations [100,104].…”

Section: Protein Stabilitymentioning

confidence: 99%

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Protein folding: Then and now

Chen

Ding

Nie

et al. 2008

Archives of Biochemistry and Biophysics

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Over the past three decades the protein folding field has undergone monumental changes. Originally a purely academic question, how a protein folds has now become vital in understanding diseases and our abilities to rationally manipulate cellular life by engineering protein folding pathways. We review and contrast past and recent developments in the protein folding field. Specifically, we discuss the progress in our understanding of protein folding thermodynamics and kinetics, the properties of evasive intermediates, and unfolded states. We also discuss how some abnormalities in protein folding lead to protein aggregation and human diseases.

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Predicting Changes in the Stability of Proteins and Protein Complexes: A Study of More Than 1000 Mutations

Cited by 1,619 publications

References 90 publications

The peptide-binding motif of HLA-DR8 shares important structural features with other type 1 diabetes-associated alleles

The peptide-binding motif of HLA-DR8 shares important structural features with other type 1 diabetes-associated alleles

Biallelic variants in LINGO1 are associated with autosomal recessive intellectual disability, microcephaly, speech and motor delay

Protein folding: Then and now

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