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Title: Predicting the Effect of Single and Multiple Mutations on Protein Structural Stability

Journal Article · · Molecules
 [1];  [2];  [2];  [2];  [1];  [1];  [3];  [2]
  1. Univ. of Massachusetts Boston, MA (United States). Dept. of Computer Science
  2. Western Washington Univ., Bellingham, WA (United States). Dept. of Computer Science
  3. Western Washington Univ., Bellingham, WA (United States). Dept. of Computer Science; Pacific Northwest National Lab. (PNNL), Richland, WA (United States). Computing and Analytics Division
+ Show Author Affiliations

Predicting how a point mutation alters a protein’s stability can guide pharmaceutical drug design initiatives which aim to counter the effects of serious diseases. Conducting mutagenesis studies in physical proteins can give insights about the effects of amino acid substitutions, but such wet-lab work is prohibitive due to the time as well as financial resources needed to assess the effect of even a single amino acid substitution. Computational methods for predicting the effects of a mutation on a protein structure can complement wet-lab work, and varying approaches are available with promising accuracy rates. In this work we compare and assess the utility of several machine learning methods and their ability to predict the effects of single and double mutations. We in silico generate mutant protein structures, and compute several rigidity metrics for each of them. We use these as features for our Support Vector Regression (SVR), Random Forest (RF), and Deep Neural Network (DNN) methods. We validate the predictions of our in silico mutations against experimental ΔΔG stability data, and attain Pearson Correlation values upwards of 0.71 for single mutations, and 0.81 for double mutations. We perform ablation studies to assess which features contribute most to a model’s success, and also introduce a voting scheme to synthesize a single prediction from the individual predictions of the three models.

Research Organization:
Pacific Northwest National Laboratory (PNNL), Richland, WA (United States)
Sponsoring Organization:
USDOE Office of Science (SC)
Grant/Contract Number:
AC05-76RL01830
OSTI ID:
1628486
Journal Information:
Molecules, Vol. 23, Issue 2; ISSN 1420-3049
Publisher:
MDPICopyright Statement
Country of Publication:
United States
Language:
English

References (63)

Contributions of hydrogen bonds of Thr 157 to the thermodynamic stability of phage T4 lysozyme journal November 1987
Contributions of hydrogen bonds of Thr 157 to the thermodynamic stability of phage T4 lysozyme journal November 1987
Dissection of helix capping in T4 lysozyme by structural and thermodynamic analysis of six amino acid substitutions at Thr 59 journal April 1992
Prediction of the stability of protein mutants based on structural environment-dependent amino acid substitution and propensity tables journal January 1997
Predicting protein stability changes upon mutation using database-derived potentials: solvent accessibility determines the importance of local versus non-local interactions along the sequence journal September 1997
Improved prediction of protein side-chain conformations with SCWRL4 journal December 2009
Subsemble: an ensemble method for combining subset-specific algorithm fits journal November 2013
Dissection of helix capping in T4 lysozyme by structural and thermodynamic analysis of six amino acid substitutions at Thr 59 journal April 1992
Scalable molecular dynamics with NAMD journal January 2005
PhosPred-RF: A Novel Sequence-Based Predictor for Phosphorylation Sites Using Sequential Information Only journal June 2017
Predicting protein stability changes upon mutation using database-derived potentials: solvent accessibility determines the importance of local versus non-local interactions along the sequence journal September 1997
Fast Prediction of Protein Methylation Sites Using a Sequence-Based Feature Selection Technique journal July 2019
Prediction of protein stability changes for single-site mutations using support vector machines journal December 2005
Response of a protein structure to cavity-creating mutations and its relation to the hydrophobic effect journal January 1992
PROTS-RF: A Robust Model for Predicting Mutation-Induced Protein Stability Changes journal October 2012
Improved prediction of protein side-chain conformations with SCWRL4 journal December 2009
Prediction of the stability of protein mutants based on structural environment-dependent amino acid substitution and propensity tables journal January 1997
Subsemble: an ensemble method for combining subset-specific algorithm fits journal November 2013
Exploiting the Link between Protein Rigidity and Thermostability for Data-Driven Protein Engineering journal October 2008
Structural basis of Fabry disease journal September 2002
ProTherm and ProNIT: thermodynamic databases for proteins and protein-nucleic acid interactions journal January 2006
Contributions of left-handed helical residues to the structure and stability of bacteriophage T4 lysozyme journal November 1989
Conformation of amino acid side-chains in proteins journal November 1978
Contribution of the hydrophobic effect to protein stability: analysis based on simulations of the Ile-96----Ala mutation in barnase. journal December 1991
Using Rigidity Analysis to Probe Mutation-Induced Structural Changes in Proteins journal June 2012
Stacked regressions journal July 1996
Conformation of amino acid side-chains in proteins journal November 1978
The effect of acidic pH on the adsorption and lytic activity of the peptides Polybia-MP1 and its histidine-containing analog in anionic lipid membrane: a biophysical study by molecular dynamics and spectroscopy journal April 2021
Prediction of protein stability changes for single-site mutations using support vector machines journal December 2005
SDM--a server for predicting effects of mutations on protein stability and malfunction journal May 2011
Protein flexibility predictions using graph theory journal January 2001
Exploiting the Link between Protein Rigidity and Thermostability for Data-Driven Protein Engineering journal October 2008
PROTS-RF: A Robust Model for Predicting Mutation-Induced Protein Stability Changes journal October 2012
Hydrophobic stabilization in T4 lysozyme determined directly by multiple substitutions of Ile 3 journal August 1988
Predicting the Effect of Mutations on Protein-Protein Binding Interactions through Structure-Based Interface Profiles journal October 2015
HPSLPred: An Ensemble Multi-Label Classifier for Human Protein Subcellular Location Prediction with Imbalanced Source journal September 2017
Predicting the Effect of Mutations on Protein-Protein Binding Interactions through Structure-Based Interface Profiles journal October 2015
KINARI-Web: a server for protein rigidity analysis journal June 2011
Super Learner journal January 2007
Tertiary templates for proteins journal February 1987
Structure Based Thermostability Prediction Models for Protein Single Point Mutations with Machine Learning Tools journal September 2015
ProMuteHT conference August 2017
Combining Estimates in Regression and Classification journal December 1996
ProTherm and ProNIT: thermodynamic databases for proteins and protein-nucleic acid interactions journal January 2006
Combining Estimates in Regression and Classification journal December 1996
Accurate prediction of the stability and activity effects of site-directed mutagenesis on a protein core journal August 1991
Contributions of all 20 amino acids at site 96 to the stability and structure of T4 lysozyme journal May 2009
LIBSVM: A library for support vector machines journal April 2011
LIBSVM: A library for support vector machines journal April 2011
Super Learner journal January 2007
Protein flexibility predictions using graph theory journal January 2001
Accurate prediction of the stability and activity effects of site-directed mutagenesis on a protein core journal August 1991
SDM--a server for predicting effects of mutations on protein stability and malfunction journal May 2011
KINARI-Web: a server for protein rigidity analysis journal June 2011
A conservation and rigidity based method for detecting critical protein residues journal January 2013
Conformational analysis of the backbone-dependent rotamer preferences of protein sidechains journal May 1994
Random Forests journal January 2001
HPSLPred: An Ensemble Multi-Label Classifier for Human Protein Subcellular Location Prediction with Imbalanced Source journal September 2017
Contributions of left-handed helical residues to the structure and stability of bacteriophage T4 lysozyme journal November 1989
An Evolutionary Conservation & Rigidity Analysis Machine Learning Approach for Detecting Critical Protein Residues
  • Jagodzinski, Filip; Akbal-Delibas, Bahar; Haspel, Nurit
  • Proceedings of the International Conference on Bioinformatics, Computational Biology and Biomedical Informatics https://doi.org/10.1145/2506583.2506708
conference September 2013
Assessing how multiple mutations affect protein stability using rigid cluster size distributions conference October 2016
ProMuteHT conference August 2017
Predicting the Effect of Point Mutations on Protein Structural Stability
  • Farhoodi, Roshanak; Shelbourne, Max; Hsieh, Rebecca
  • Proceedings of the 8th ACM International Conference on Bioinformatics, Computational Biology,and Health Informatics https://doi.org/10.1145/3107411.3107492
conference August 2017

Cited By (5)

Evaluating Protein Engineering Thermostability Prediction Tools Using an Independently Generated Dataset journal March 2020
Amino-Acid Network Clique Analysis of Protein Mutation Non-Additive Effects: A Case Study of Lysozme journal May 2018
Amino-Acid Network Clique Analysis of Protein Mutation Non-Additive Effects: A Case Study of Lysozme journal May 2018
Robust Prediction of Single and Multiple Point Protein Mutations Stability Changes journal December 2019
PETRA: Drug Engineering via Rigidity Analysis journal March 2020

Figures / Tables (14)

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37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY
59 BASIC BIOLOGICAL SCIENCES
97 MATHEMATICS AND COMPUTING
Biochemistry & Molecular Biology
Chemistry
machine learning
protein mutational study
SVR
RF
DNN
rigidity analysis