Accurate and Efficient Calculation of Protein-Protein Binding Free Energy-Interaction Entropy with Residue Type-Specific Dielectric Constants

Xiao Liu, Long Peng, John Zhang

Research output: Contribution to journalArticle

Abstract

Accurate and efficient computation of protein-protein binding free energy remains a grand challenge. In this study, we develop a new strategy to achieve efficient calculation for total protein-protein binding free energies with improved accuracy. The new method combines the recently developed interaction entropy method for efficient computation of entropic change together with the use of residue type-specific dielectric constants in the framework of MM/GBSA to achieve optimal result for protein-protein binding free energies. The new strategy is shown to be computationally efficient and accurate than that using standard MM/GBSA methods in which the entropic computation is performed by the normal model approach and the protein interior is represented by the standard dielectric constant (typically set to 1), both in terms of accuracy and computational efficiency. Our study using the new strategy on a set of randomly selected 20 protein-protein binding systems produced an optimal dielectric constant of 2.7 for charged residues and 1.1 for noncharged residues. Using this new strategy, the mean absolute error in computed binding free energies for these 20 selected protein-protein systems is significantly reduced by more than 3-fold while the computational cost is reduced by more than 2 orders of magnitude, compared to the result using standard MM/GBSA method with the normal mode approach. A similar improvement in accuracy is confirmed for a test set consisting of 10 protein-protein systems.

Original languageEnglish (US)
Pages (from-to)272-281
Number of pages10
JournalJournal of Chemical Information and Modeling
Volume59
Issue number1
DOIs
StatePublished - Jan 28 2019

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entropy
Free energy
Permittivity
Entropy
Proteins
energy
interaction
efficiency
Protein Binding
costs
Computational efficiency

ASJC Scopus subject areas

  • Chemistry(all)
  • Chemical Engineering(all)
  • Computer Science Applications
  • Library and Information Sciences

Cite this

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title = "Accurate and Efficient Calculation of Protein-Protein Binding Free Energy-Interaction Entropy with Residue Type-Specific Dielectric Constants",
abstract = "Accurate and efficient computation of protein-protein binding free energy remains a grand challenge. In this study, we develop a new strategy to achieve efficient calculation for total protein-protein binding free energies with improved accuracy. The new method combines the recently developed interaction entropy method for efficient computation of entropic change together with the use of residue type-specific dielectric constants in the framework of MM/GBSA to achieve optimal result for protein-protein binding free energies. The new strategy is shown to be computationally efficient and accurate than that using standard MM/GBSA methods in which the entropic computation is performed by the normal model approach and the protein interior is represented by the standard dielectric constant (typically set to 1), both in terms of accuracy and computational efficiency. Our study using the new strategy on a set of randomly selected 20 protein-protein binding systems produced an optimal dielectric constant of 2.7 for charged residues and 1.1 for noncharged residues. Using this new strategy, the mean absolute error in computed binding free energies for these 20 selected protein-protein systems is significantly reduced by more than 3-fold while the computational cost is reduced by more than 2 orders of magnitude, compared to the result using standard MM/GBSA method with the normal mode approach. A similar improvement in accuracy is confirmed for a test set consisting of 10 protein-protein systems.",
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