Predicting protein‐DNA binding free energy change upon missense mutations using modified MM/PBSA approach: SAMPDI webserver

Motivation Protein‐DNA interactions are essential for regulating many cellular processes, such as transcription, replication, recombination and translation. Amino acid mutations occurring in DNA‐binding proteins have profound effects on protein‐DNA binding and are linked with many diseases. Hence, accurate and fast predictions of the effects of mutations on protein‐DNA binding affinity are essential for understanding disease‐causing mechanisms and guiding plausible treatments. Results Here we report a new method Single Amino acid Mutation binding free energy change of Protein‐DNA Interaction (SAMPDI). The method utilizes modified Molecular Mechanics Poisson‐Boltzmann Surface Area (MM/PBSA) approach along with an additional set of knowledge‐based terms delivered from investigations of the physicochemical properties of protein‐DNA complexes. The method is benchmarked against experimentally determined binding free energy changes caused by 105 mutations in 13 proteins (compiled ProNIT database and data from recent references), and results in correlation coefficient of 0.72. Availability and implementation http://compbio.clemson.edu/SAMPDI Contact ealexov@clemson.edu Supplementary information Supplementary data are available at Bioinformatics online.

[1]  Roland L. Dunbrack,et al.  A smoothed backbone-dependent rotamer library for proteins derived from adaptive kernel density estimates and regressions. , 2011, Structure.

[2]  Stephen T. C. Wong,et al.  MeCP2, a Key Contributor to Neurological Disease, Activates and Represses Transcription , 2008, Science.

[3]  G. Orphanides,et al.  A Unified Theory of Gene Expression , 2002, Cell.

[4]  R. H. Austin,et al.  Importance of DNA stiffness in protein–DNA binding specificity , 1987, Nature.

[5]  Douglas E. V. Pires,et al.  mCSM: predicting the effects of mutations in proteins using graph-based signatures , 2013, Bioinform..

[6]  Lin Li,et al.  Treating ion distribution with Gaussian‐based smooth dielectric function in DelPhi , 2017, J. Comput. Chem..

[7]  David S. Goodsell,et al.  The RCSB Protein Data Bank: views of structural biology for basic and applied research and education , 2014, Nucleic Acids Res..

[8]  Karen H. Vousden,et al.  p53 in health and disease , 2007, Nature Reviews Molecular Cell Biology.

[9]  Alexander D. MacKerell,et al.  Impact of 2′‐hydroxyl sampling on the conformational properties of RNA: Update of the CHARMM all‐atom additive force field for RNA , 2011, J. Comput. Chem..

[10]  Janet M Thornton,et al.  Using electrostatic potentials to predict DNA-binding sites on DNA-binding proteins. , 2003, Nucleic acids research.

[11]  Tingjun Hou,et al.  Assessing the Performance of the MM/PBSA and MM/GBSA Methods. 1. The Accuracy of Binding Free Energy Calculations Based on Molecular Dynamics Simulations , 2011, J. Chem. Inf. Model..

[12]  Alexander D. MacKerell,et al.  Optimization of the additive CHARMM all-atom protein force field targeting improved sampling of the backbone φ, ψ and side-chain χ(1) and χ(2) dihedral angles. , 2012, Journal of chemical theory and computation.

[13]  Akinori Sarai,et al.  ProTherm and ProNIT: thermodynamic databases for proteins and protein–nucleic acid interactions , 2005, Nucleic Acids Res..

[14]  H M Berman,et al.  Protein-DNA interactions: A structural analysis. , 1999, Journal of molecular biology.

[15]  E. Alexov,et al.  Computational investigation of proton transfer, pKa shifts and pH‐optimum of protein–DNA and protein–RNA complexes , 2017, Proteins.

[16]  Tugba G. Kucukkal,et al.  Mutations in the KDM5C ARID Domain and Their Plausible Association with Syndromic Claes-Jensen-Type Disease , 2015, International journal of molecular sciences.

[17]  Nicholas M. Luscombe,et al.  Amino acid?base interactions: a three-dimensional analysis of protein?DNA interactions at an atomic level , 2001, Nucleic Acids Res..

[18]  R. Clubb,et al.  NMR structure of the Tn916 integrase–DNA complex , 1999, Nature Structural Biology.

[19]  Tugba G. Kucukkal,et al.  On Human Disease‐Causing Amino Acid Variants: Statistical Study of Sequence and Structural Patterns , 2015, Human mutation.

[20]  Janet M Thornton,et al.  Protein-DNA interactions: amino acid conservation and the effects of mutations on binding specificity. , 2002, Journal of molecular biology.

[21]  R. Mann,et al.  Origins of specificity in protein-DNA recognition. , 2010, Annual review of biochemistry.

[22]  Chuan Li,et al.  Continuous development of schemes for parallel computing of the electrostatics in biological systems: Implementation in DelPhi , 2013, J. Comput. Chem..

[23]  Emil Alexov,et al.  Predicting Binding Free Energy Change Caused by Point Mutations with Knowledge-Modified MM/PBSA Method , 2015, PLoS Comput. Biol..

[24]  Tingjun Hou,et al.  Assessing the performance of the molecular mechanics/Poisson Boltzmann surface area and molecular mechanics/generalized Born surface area methods. II. The accuracy of ranking poses generated from docking , 2011, J. Comput. Chem..

[25]  Song Liu,et al.  A knowledge-based energy function for protein-ligand, protein-protein, and protein-DNA complexes. , 2005, Journal of medicinal chemistry.

[26]  L. Mirny,et al.  Kinetics of protein-DNA interaction: facilitated target location in sequence-dependent potential. , 2004, Biophysical journal.

[27]  Emil Alexov,et al.  On the Modeling of Polar Component of Solvation Energy using Smooth Gaussian-Based Dielectric Function. , 2014, Journal of theoretical & computational chemistry.

[28]  Pierre Gönczy,et al.  A single amino acid can determine the DNA binding specificity of homeodomain proteins , 1989, Cell.

[29]  Marianne Rooman,et al.  BeAtMuSiC: prediction of changes in protein–protein binding affinity on mutations , 2013, Nucleic Acids Res..

[30]  David B. Ascher,et al.  mCSM–NA: predicting the effects of mutations on protein–nucleic acids interactions , 2017, Nucleic Acids Res..

[31]  J. Schildbach,et al.  Inter- and intramolecular determinants of the specificity of single-stranded DNA binding and cleavage by the F factor relaxase. , 2005, Structure.

[32]  Anna R. Panchenko,et al.  MutaBind estimates and interprets the effects of sequence variants on protein–protein interactions , 2016, Nucleic Acids Res..

[33]  M R Lee,et al.  Use of MM‐PB/SA in estimating the free energies of proteins: Application to native, intermediates, and unfolded villin headpiece , 2000, Proteins.

[34]  Haruki Nakamura,et al.  Solution structure of a specific DNA complex of the Myb DNA-binding domain with cooperative recognition helices , 1994, Cell.

[35]  Xiaodi Su,et al.  Characterization of protein--DNA interactions using surface plasmon resonance spectroscopy with various assay schemes. , 2007, Biochemistry.

[36]  R. Roeder,et al.  Role of general and gene-specific cofactors in the regulation of eukaryotic transcription. , 1998, Cold Spring Harbor symposia on quantitative biology.

[37]  S. Campagne,et al.  Nuclear magnetic resonance analysis of protein–DNA interactions , 2011, Journal of The Royal Society Interface.

[38]  R. Mann,et al.  The role of DNA shape in protein-DNA recognition , 2009, Nature.

[39]  Eric J. Bohm,et al.  Scalable Molecular Dynamics with NAMD on Blue Gene / L , 2012 .

[40]  J. Tellinghuisen.  Isothermal titration calorimetry at very low c. , 2008, Analytical biochemistry.

[41]  Jason E. Donald,et al.  Energetics of protein–DNA interactions , 2006, Nucleic acids research.

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

[43]  D. Baker,et al.  Protein–DNA binding specificity predictions with structural models , 2005, Nucleic acids research.

[44]  E. Alexov,et al.  SAAFEC: Predicting the Effect of Single Point Mutations on Protein Folding Free Energy Using a Knowledge-Modified MM/PBSA Approach , 2016, International journal of molecular sciences.

[45]  Yang Zhang,et al.  Predicting the Effect of Mutations on Protein-Protein Binding Interactions through Structure-Based Interface Profiles , 2015, PLoS Comput. Biol..

[46]  E. Alexov,et al.  Investigating the linkage between disease‐causing amino acid variants and their effect on protein stability and binding , 2016, Proteins.

[47]  D. Srivastava,et al.  Mutations in NOTCH1 cause aortic valve disease , 2005, Nature.

[48]  E. Bochkareva,et al.  The 2.2 A structure of a permanganate-sensitive DNA site bound by the Epstein-Barr virus origin binding protein, EBNA1. , 1998, Journal of molecular biology.

[49]  Jun-tao Guo,et al.  Quantitative evaluation of protein–DNA interactions using an optimized knowledge-based potential , 2005, Nucleic acids research.

[50]  S. Diekmann,et al.  Recent advances in FRET: distance determination in protein-DNA complexes. , 2001, Current opinion in structural biology.

[51]  K Schulten,et al.  VMD: visual molecular dynamics. , 1996, Journal of molecular graphics.