Defining the Specificity of Carbohydrate-Protein Interactions by Quantifying Functional Group Contributions

Amika Sood; Oksana O. Gerlits; Ye Ji; Nicolai V. Bovin; Leighton Coates; Robert J. Woods

doi:10.1021/acs.jcim.8b00120

Defining the Specificity of Carbohydrate-Protein Interactions by Quantifying Functional Group Contributions

Amika Sood, Oksana O. Gerlits, Ye Ji, Nicolai V. Bovin, Leighton Coates, Robert J. Woods

STS Project Technical Systems

Research output: Contribution to journal › Article › peer-review

20 Scopus citations

Abstract

Protein-carbohydrate interactions are significant in a wide range of biological processes, disruption of which has been implicated in many different diseases. The capability of glycan-binding proteins (GBPs) to specifically bind to the corresponding glycans allows GBPs to be utilized in glycan biomarker detection or conversely to serve as targets for therapeutic intervention. However, understanding the structural origins of GBP specificity has proven to be challenging due to their typically low binding affinities (mM) and their potential to display broad or complex specificities. Here we perform molecular dynamics (MD) simulations and post-MD energy analyses with the Poisson-Boltzmann and generalized Born solvent models (MM-PB/GBSA) of the Erythrina cristagalli lectin (ECL) with its known ligands, and with new cocrystal structures reported herein. While each MM-PB/GBSA parametrization resulted in different estimates of the desolvation free energy, general trends emerged that permit us to define GBP binding preferences in terms of ligand substructure specificity. Additionally, we have further decomposed the theoretical interaction energies into contributions made between chemically relevant functional groups. Based on these contributions, the functional groups in each ligand can be assembled into a pharmacophore comprised of groups that are either critical for binding, or enhance binding, or are noninteracting. It is revealed that the pharmacophore for ECL consists of the galactopyranose (Gal) ring atoms along with C6 and the O3 and O4 hydroxyl groups. This approach provides a convenient method for identifying and quantifying the glycan pharmacophore and provides a novel method for interpreting glycan specificity that is independent of residue-level glycan nomenclature. A pharmacophore approach to defining specificity is readily transferable to molecular design software and, therefore, may be particularly useful in designing therapeutics (glycomimetics) that target GBPs.

Original language	English
Pages (from-to)	1889-1901
Number of pages	13
Journal	Journal of Chemical Information and Modeling
Volume	58
Issue number	9
DOIs	https://doi.org/10.1021/acs.jcim.8b00120
State	Published - Sep 24 2018

Funding

*Mailing address: 315 Riverbend Road, Athens, GA 30602. Tel.: 706-542-4454. Fax: 706-542-4412. E-mail: rwoods@ccrc. uga.edu (R.J.W.). ORCID Leighton Coates: 0000-0003-2342-049X Robert J. Woods: 0000-0002-2400-6293 Author Contributions ⊥A.S., O.O.G., Y.J. contributed equally to the research. A.S., Y.J., O.O.G., and R.J.W. designed the research; A.S., Y.J., L.C., and O.O.G. performed the research; N.V.B. provided reagents; A.S., Y.J., O.O.G., L.C., and R.J.W. analyzed data; A.S. and R.J.W. wrote the paper. Funding The authors thank the National Institutes of Health for support (U01 CA207824, P41 GM103390). Crystallographic results shown in this report are partly derived from work performed at Argonne National Laboratory, Structural Biology Center (SBC) at the Advanced Photon Source. SBC-CAT is operated by UChicago Argonne, LLC, for the U.S. Department of Energy, Office of Biological and Environmental Research under contract DE-AC02-06CH11357. Research at the Spallation Neutron Source (SNS) at ORNL was sponsored by the Scientific User Facilities Division, Office of Basic Energy Sciences, U.S. Department of Energy. The Office of Biological and Environmental Research supported research at the Center for Structural Molecular Biology (CSMB) at ORNL using facilities supported by the Scientific User Facilities Division, Office of Basic Energy Sciences, U.S. Department of Energy. 2′-Fucosyl-N-acetyllactosamine was kindly provided by Consortium for Functional Glycomics. Notes The authors declare no competing financial interest.

Funders	Funder number
Center for Structural Molecular Biology
Office of Basic Energy Sciences
Office of Biological and Environmental Research	DE-AC02-06CH11357
Scientific User Facilities Division
National Institutes of Health	P41 GM103390
U.S. Department of Energy
National Cancer Institute	U01CA207824
Basic Energy Sciences
Canadian Society for Molecular Biosciences

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10.1021/acs.jcim.8b00120

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title = "Defining the Specificity of Carbohydrate-Protein Interactions by Quantifying Functional Group Contributions",

abstract = "Protein-carbohydrate interactions are significant in a wide range of biological processes, disruption of which has been implicated in many different diseases. The capability of glycan-binding proteins (GBPs) to specifically bind to the corresponding glycans allows GBPs to be utilized in glycan biomarker detection or conversely to serve as targets for therapeutic intervention. However, understanding the structural origins of GBP specificity has proven to be challenging due to their typically low binding affinities (mM) and their potential to display broad or complex specificities. Here we perform molecular dynamics (MD) simulations and post-MD energy analyses with the Poisson-Boltzmann and generalized Born solvent models (MM-PB/GBSA) of the Erythrina cristagalli lectin (ECL) with its known ligands, and with new cocrystal structures reported herein. While each MM-PB/GBSA parametrization resulted in different estimates of the desolvation free energy, general trends emerged that permit us to define GBP binding preferences in terms of ligand substructure specificity. Additionally, we have further decomposed the theoretical interaction energies into contributions made between chemically relevant functional groups. Based on these contributions, the functional groups in each ligand can be assembled into a pharmacophore comprised of groups that are either critical for binding, or enhance binding, or are noninteracting. It is revealed that the pharmacophore for ECL consists of the galactopyranose (Gal) ring atoms along with C6 and the O3 and O4 hydroxyl groups. This approach provides a convenient method for identifying and quantifying the glycan pharmacophore and provides a novel method for interpreting glycan specificity that is independent of residue-level glycan nomenclature. A pharmacophore approach to defining specificity is readily transferable to molecular design software and, therefore, may be particularly useful in designing therapeutics (glycomimetics) that target GBPs.",

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Defining the Specificity of Carbohydrate-Protein Interactions by Quantifying Functional Group Contributions

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