Free-Energy-Based Protein Design: Re-Engineering Cellular Retinoic Acid Binding Protein II Assisted by the Moveable-Type Approach

Haizhen Andrew Zhong, Elizabeth M. Santos, Chrysoula Vasileiou, Zheng Zheng, James H. Geiger, Babak Borhan, Kenneth M. Merz

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

How to fine-tune the binding free energy of a small-molecule to a receptor site by altering the amino acid residue composition is a key question in protein engineering. Indeed, the ultimate solution to this problem, to chemical accuracy (±1 kcal/mol), will result in profound and wide-ranging applications in protein design. Numerous tools have been developed to address this question using knowledge-based models to more computationally intensive molecular dynamics simulations-based free energy calculations, but while some success has been achieved there remains room for improvement in terms of overall accuracy and in the speed of the methodology. Here we report a fast, knowledge-based movable-type (MT)-based approach to estimate the absolute and relative free energy of binding as influenced by mutations in a small-molecule binding site in a protein. We retrospectively validate our approach using mutagenesis data for retinoic acid binding to the Cellular Retinoic Acid Binding Protein II (CRABPII) system and then make prospective predictions that are borne out experimentally. The overall performance of our approach is supported by its success in identifying mutants that show high or even sub-nano-molar binding affinities of retinoic acid to the CRABPII system.

Original languageEnglish (US)
Pages (from-to)3483-3486
Number of pages4
JournalJournal of the American Chemical Society
Volume140
Issue number10
DOIs
StatePublished - Mar 14 2018

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Tretinoin
Free energy
Proteins
Protein Engineering
Acids
Molecular Dynamics Simulation
Mutagenesis
Molecules
Binding Sites
Amino Acids
Mutation
Molecular dynamics
Binding sites
Amino acids
Computer simulation
Chemical analysis
cellular retinoic acid binding protein II
Carrier Proteins

ASJC Scopus subject areas

  • Catalysis
  • Chemistry(all)
  • Biochemistry
  • Colloid and Surface Chemistry

Cite this

Free-Energy-Based Protein Design : Re-Engineering Cellular Retinoic Acid Binding Protein II Assisted by the Moveable-Type Approach. / Zhong, Haizhen Andrew; Santos, Elizabeth M.; Vasileiou, Chrysoula; Zheng, Zheng; Geiger, James H.; Borhan, Babak; Merz, Kenneth M.

In: Journal of the American Chemical Society, Vol. 140, No. 10, 14.03.2018, p. 3483-3486.

Research output: Contribution to journalArticle

Zhong, Haizhen Andrew ; Santos, Elizabeth M. ; Vasileiou, Chrysoula ; Zheng, Zheng ; Geiger, James H. ; Borhan, Babak ; Merz, Kenneth M. / Free-Energy-Based Protein Design : Re-Engineering Cellular Retinoic Acid Binding Protein II Assisted by the Moveable-Type Approach. In: Journal of the American Chemical Society. 2018 ; Vol. 140, No. 10. pp. 3483-3486.
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