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Improving homology modeling of G-protein coupled receptors through multiple-template derived conserved inter-residue interactions

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Abstract

Evidenced by the three-rounds of G-protein coupled receptors (GPCR) Dock competitions, improving homology modeling methods of helical transmembrane proteins including the GPCRs, based on templates of low sequence identity, remains an eminent challenge. Current approaches addressing this challenge adopt the philosophy of “modeling first, refinement next”. In the present work, we developed an alternative modeling approach through the novel application of available multiple templates. First, conserved inter-residue interactions are derived from each additional template through conservation analysis of each template-target pairwise alignment. Then, these interactions are converted into distance restraints and incorporated in the homology modeling process. This approach was applied to modeling of the human β2 adrenergic receptor using the bovin rhodopsin and the human protease-activated receptor 1 as templates and improved model quality was demonstrated compared to the homology model generated by standard single-template and multiple-template methods. This method of “refined restraints first, modeling next”, provides a fast and complementary way to the current modeling approaches. It allows rational identification and implementation of additional conserved distance restraints extracted from multiple templates and/or experimental data, and has the potential to be applicable to modeling of all helical transmembrane proteins.

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Acknowledgments

We thank our anonymous reviewers for constructive comments. This work was supported by the NIH Grant R15-GM084404 and NSF 1229564 award.

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Authors and Affiliations

  1. Department of Chemistry & Biochemistry, University of the Sciences in Philadelphia, Box 48, Philadelphia, PA, 19104, USA

    Rajan Chaudhari, Andrew J. Heim & Zhijun Li

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  1. Rajan Chaudhari
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  2. Andrew J. Heim
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  3. Zhijun Li
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Correspondence to Zhijun Li.

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Chaudhari, R., Heim, A.J. & Li, Z. Improving homology modeling of G-protein coupled receptors through multiple-template derived conserved inter-residue interactions. J Comput Aided Mol Des 29, 413–420 (2015). https://doi.org/10.1007/s10822-014-9823-2

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