Prediction of change in protein unfolding rates upon point mutations in two state proteins.
Studies on protein unfolding rates are limited and challenging due to the complexity of unfolding mechanism and the larger dynamic range of the experimental data. Though attempts have been made to predict unfolding rates using protein sequence-structure information there is no available method for predicting the unfolding rates of proteins upon specific point mutations. In this work, we have systematically analyzed a set of 790 single mutants and developed a robust method for predicting protein unfolding rates upon mutations (Δlnku) in two-state proteins by combining amino acid properties and knowledge-based classification of mutants with multiple linear regression technique. We obtain a mean absolute error (MAE) of 0.79/s and a Pearson correlation coefficient (PCC) of 0.71 between predicted unfolding rates and experimental observations using jack-knife test. We have developed a web server for predicting protein unfolding rates upon mutation and it is freely available at https://www.iitm.ac.in/bioinfo/proteinunfolding/unfoldingrace.html. Prominent features that determine unfolding kinetics as well as plausible reasons for the observed outliers are also discussed.
Department of Biotechnology, Bhupat & Jyoti Mehta School of Biosciences, Indian Institute of Technology Madras, Chennai 600 036, Tamil Nadu, India.
Priyashree
P
Chaudhary
Department of Biotechnology, Bhupat & Jyoti Mehta School of Biosciences, Indian Institute of Technology Madras, Chennai 600 036, Tamil Nadu, India.
Athi N
AN
Naganathan
Department of Biotechnology, Bhupat & Jyoti Mehta School of Biosciences, Indian Institute of Technology Madras, Chennai 600 036, Tamil Nadu, India. Electronic address: gromiha@iitm.ac.in.
M Michael
MM
Gromiha
D000596:Amino Acids / Q000737:chemistry*; D006801:Humans; D007700:Kinetics; D016014:Linear Models; D017354:Point Mutation; D000072756:Protein Conformation, alpha-Helical; D000072757:Protein Conformation, beta-Strand; D017510:Protein Folding; D054730:Protein Interaction Domains and Motifs; D017434:Protein Structure, Tertiary; D058767:Protein Unfolding; D011506:Proteins / Q000737:chemistry*; D013816:Thermodynamics
D000596:Amino Acids; D011506:Proteins
Amino acid properties; Machine learning; Multiple regression technique; Point mutations; Two-state proteins; Unfolding rates