Structural assessment of the effects of Amino Acid Substitutions on protein stability and protein-protein interaction

A structure-based approach is described for predicting the effects of amino acid substitutions on protein function. Structures were predicted using a homology modelling method. Folding and binding energy differences between wild-type and mutant structures were computed to quantitatively assess the effects of amino acid substitutions on protein stability and protein protein interaction, respectively. We demonstrated that pathogenic mutations at the interaction interface could affect binding energy and destabilise protein complex, whereas mutations at the non-interface might reduce folding energy and destabilise monomer structure. The results suggest that the structure-based analysis can provide useful information for understanding the molecular mechanisms of diseases.

[1]  K. Dill,et al.  Cooperativity in protein-folding kinetics. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[2]  M. Cargill.  Characterization of single-nucleotide polymorphisms in coding regions of human genes , 1999, Nature Genetics.

[3]  Carlos Bustamante,et al.  Inferring SNP function using evolutionary, structural, and computational methods. , 2005 .

[4]  Z. Xiang,et al.  Extending the accuracy limits of prediction for side-chain conformations. , 2001, Journal of molecular biology.

[5]  Timothy Lynch,et al.  Identification of a novel LRRK2 mutation linked to autosomal dominant parkinsonism: evidence of a common founder across European populations. , 2005, American journal of human genetics.

[6]  D. Chui,et al.  Hydrops Fetalis Caused by α-Thalassemia: An Emerging Health Care Problem , 1998 .

[7]  Hongyi Zhou,et al.  Distance‐scaled, finite ideal‐gas reference state improves structure‐derived potentials of mean force for structure selection and stability prediction , 2002, Protein science : a publication of the Protein Society.

[8]  Gregory D. Schuler,et al.  Database resources of the National Center for Biotechnology Information: update , 2004, Nucleic acids research.

[9]  Matthew J. Farrer,et al.  LRRK2 in Parkinson's disease: protein domains and functional insights , 2006, Trends in Neurosciences.

[10]  A. Marabotti,et al.  Analysis of galactosemia-linked mutations of GALT enzyme using a computational biology approach. , 2010, Protein engineering, design & selection : PEDS.

[11]  Liang-Tsung Huang,et al.  iPTREE-STAB: interpretable decision tree based method for predicting protein stability changes upon mutations , 2007, Bioinform..

[12]  N O Stitziel,et al.  STRUCTURAL LOCATION OF DISEASEASSOCIATED SINGLE-NUCLEOTIDE POLYMORPHISMS , 2003 .

[13]  Yuri E Nikiforov,et al.  RAS point mutations and PAX8-PPAR gamma rearrangement in thyroid tumors: evidence for distinct molecular pathways in thyroid follicular carcinoma. , 2003, The Journal of clinical endocrinology and metabolism.

[14]  M. Miller,et al.  Understanding human disease mutations through the use of interspecific genetic variation. , 2001, Human molecular genetics.

[15]  Mauno Vihinen,et al.  Performance of protein stability predictors , 2010, Human mutation.

[16]  D. Chui,et al.  Hydrops fetalis caused by alpha-thalassemia: an emerging health care problem. , 1998, Blood.

[17]  J. Moult,et al.  SNPs, protein structure, and disease , 2001, Human mutation.

[18]  François Stricher,et al.  The FoldX web server: an online force field , 2005, Nucleic Acids Res..

[19]  Emil Alexov,et al.  Modeling effects of human single nucleotide polymorphisms on protein-protein interactions. , 2009, Biophysical journal.

[20]  Elizabeth M. Smigielski,et al.  dbSNP: a database of single nucleotide polymorphisms , 2000, Nucleic Acids Res..

[21]  Lei Xie,et al.  Using multiple structure alignments, fast model building, and energetic analysis in fold recognition and homology modeling , 2003, Proteins.

[22]  Liangjiang Wang,et al.  Sequence feature-based prediction of protein stability changes upon amino acid substitutions , 2010, BMC Genomics.

[23]  Philippe Bogaerts,et al.  Fast and accurate predictions of protein stability changes upon mutations using statistical potentials and neural networks: PoPMuSiC-2.0 , 2009, Bioinform..

[24]  Shuangye Yin,et al.  Eris: an automated estimator of protein stability , 2007, Nature Methods.

[25]  Steven Henikoff,et al.  SIFT: predicting amino acid changes that affect protein function , 2003, Nucleic Acids Res..

[26]  Z. Xiang,et al.  Advances in homology protein structure modeling. , 2006, Current protein & peptide science.

[27]  Zhe Zhang,et al.  Computational analysis of missense mutations causing Snyder‐Robinson syndrome , 2010, Human mutation.

[28]  J. Moult,et al.  Identification and analysis of deleterious human SNPs. , 2006, Journal of molecular biology.

[29]  Y W Kan.  Molecular biology of hemoglobin: its application to sickle cell anemia and thalassemia. , 1991, Schweizerische medizinische Wochenschrift. Supplementum.

[30]  M. Karplus,et al.  CHARMM: A program for macromolecular energy, minimization, and dynamics calculations , 1983 .

[31]  Mathias Toft,et al.  LRRK2 mutations and Parkinsonism , 2005, The Lancet.

[32]  Michael J. Grusby,et al.  Zinc Finger Protein Zbtb20 Is Essential for Postnatal Survival and Glucose Homeostasis , 2009, Molecular and Cellular Biology.

[33]  Gennady Verkhivker,et al.  Computational modeling of structurally conserved cancer mutations in the RET and MET kinases: the impact on protein structure, dynamics, and stability. , 2009, Biophysical journal.

[34]  S. Kasif,et al.  Structural location of disease-associated single-nucleotide polymorphisms. , 2003, Journal of molecular biology.

[35]  Rodrigo Lopez,et al.  Clustal W and Clustal X version 2.0 , 2007, Bioinform..

[36]  Claudio Carta,et al.  Diversity, parental germline origin, and phenotypic spectrum of de novo HRAS missense changes in Costello syndrome , 2007, Human mutation.

[37]  Hwangseo Park,et al.  Prediction of the mutation-induced change in thermodynamic stabilities of membrane proteins from free energy simulations. , 2005, Biophysical chemistry.

[38]  Mathias Toft,et al.  Clinical features of LRRK2‐associated Parkinson's disease in central Norway , 2005, Annals of neurology.

[39]  E. Alexov,et al.  Approaches and resources for prediction of the effects of non-synonymous single nucleotide polymorphism on protein function and interactions. , 2008, Current pharmaceutical biotechnology.

[40]  Piero Fariselli,et al.  A three-state prediction of single point mutations on protein stability changes , 2007, BMC Bioinformatics.