TY - JOUR
T1 - Free-Energy-Based Protein Design
T2 - Re-Engineering Cellular Retinoic Acid Binding Protein II Assisted by the Moveable-Type Approach
AU - Zhong, Haizhen A.
AU - Santos, Elizabeth M.
AU - Vasileiou, Chrysoula
AU - Zheng, Zheng
AU - Geiger, James H.
AU - Borhan, Babak
AU - Merz, Kenneth M.
N1 - Funding Information:
K.M.M. thanks the NIH (GM112406) for supporting the present research. B.B. thanks the NIH (GM101353) for support. H.A.Z. thanks the Faculty Development Fellowship from University of Nebraska at Omaha.
Publisher Copyright:
© 2018 American Chemical Society.
PY - 2018/3/14
Y1 - 2018/3/14
N2 - 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.
AB - 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.
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U2 - 10.1021/jacs.7b10368
DO - 10.1021/jacs.7b10368
M3 - Article
C2 - 29480012
AN - SCOPUS:85043768532
VL - 140
SP - 3483
EP - 3486
JO - Journal of the American Chemical Society
JF - Journal of the American Chemical Society
SN - 0002-7863
IS - 10
ER -