Skip to main content
bioRxiv
  • Home
  • About
  • Submit
  • ALERTS / RSS
Advanced Search
New Results

Protein-ligand interfaces are polarized: Discovery of a strong trend for intermolecular hydrogen bonds to favor donors on the protein side with implications for predicting and designing ligand complexes

View ORCID ProfileSebastian Raschka, Alex J. Wolf, Joseph Bemister-Buffington, Leslie A. Kuhn
doi: https://doi.org/10.1101/260612
Sebastian Raschka
1Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, MI 48824, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Sebastian Raschka
Alex J. Wolf
1Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, MI 48824, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Joseph Bemister-Buffington
1Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, MI 48824, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Leslie A. Kuhn
1Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, MI 48824, USA
2Department of Computer Science and Engineering, Michigan State University, East Lansing, MI 48824, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • For correspondence: KuhnL@msu.edu
  • Abstract
  • Full Text
  • Info/History
  • Metrics
  • Supplementary material
  • Preview PDF
Loading

Abstract

Understanding how proteins encode ligand specificity is fascinating and similar in importance to deciphering the genetic code. For protein-ligand recognition, the combination of an almost infinite variety of interfacial shapes and patterns of chemical groups makes the problem especially challenging. Here we analyze data across non-homologous proteins in complex with small biological ligands to address observations made in our inhibitor discovery projects: that proteins favor donating H-bonds to ligands and avoid using groups with both H-bond donor and acceptor capacity. The resulting clear and significant chemical group matching preferences elucidate the code for protein-native ligand binding, similar to the dominant patterns found in nucleic acid base-pairing. On average, 90% of the keto and carboxylate oxygens occurring in the biological ligands formed direct H-bonds to the protein. A two-fold preference was found for protein atoms to act as H-bond donors and ligand atoms to act as acceptors, and 76% of all intermolecular H-bonds involved an amine donor. Together, the tight chemical and geometric constraints associated with satisfying donor groups generate a hydrogen-bonding lock that can be matched only by ligands bearing the right acceptor-rich key. Measuring an index of H-bond preference based on the observed chemical trends proved sufficient to predict other protein-ligand complexes and can be used to guide molecular design. The resulting Hbind and Protein Recognition Index software packages are being made available for rigorously defining intermolecular H-bonds and measuring the extent to which H-bonding patterns in a given complex match the preference key.

3D
three-dimensional
CATH
Class Architecture Topology Homologous superfamily
H-bonds
hydrogen bonds
MMFF94
Merck Molecular Force Field
PDB
Protein Data Bank
PRI
Protein Recognition Index
Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
Back to top
PreviousNext
Posted February 05, 2018.
Download PDF

Supplementary Material

Email

Thank you for your interest in spreading the word about bioRxiv.

NOTE: Your email address is requested solely to identify you as the sender of this article.

Enter multiple addresses on separate lines or separate them with commas.
Protein-ligand interfaces are polarized: Discovery of a strong trend for intermolecular hydrogen bonds to favor donors on the protein side with implications for predicting and designing ligand complexes
(Your Name) has forwarded a page to you from bioRxiv
(Your Name) thought you would like to see this page from the bioRxiv website.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Share
Protein-ligand interfaces are polarized: Discovery of a strong trend for intermolecular hydrogen bonds to favor donors on the protein side with implications for predicting and designing ligand complexes
Sebastian Raschka, Alex J. Wolf, Joseph Bemister-Buffington, Leslie A. Kuhn
bioRxiv 260612; doi: https://doi.org/10.1101/260612
Digg logo Reddit logo Twitter logo Facebook logo Google logo LinkedIn logo Mendeley logo
Citation Tools
Protein-ligand interfaces are polarized: Discovery of a strong trend for intermolecular hydrogen bonds to favor donors on the protein side with implications for predicting and designing ligand complexes
Sebastian Raschka, Alex J. Wolf, Joseph Bemister-Buffington, Leslie A. Kuhn
bioRxiv 260612; doi: https://doi.org/10.1101/260612

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
  • Tweet Widget
  • Facebook Like
  • Google Plus One

Subject Area

  • Bioinformatics
Subject Areas
All Articles
  • Animal Behavior and Cognition (4091)
  • Biochemistry (8776)
  • Bioengineering (6490)
  • Bioinformatics (23369)
  • Biophysics (11759)
  • Cancer Biology (9163)
  • Cell Biology (13259)
  • Clinical Trials (138)
  • Developmental Biology (7419)
  • Ecology (11377)
  • Epidemiology (2066)
  • Evolutionary Biology (15098)
  • Genetics (10405)
  • Genomics (14017)
  • Immunology (9132)
  • Microbiology (22076)
  • Molecular Biology (8786)
  • Neuroscience (47408)
  • Paleontology (350)
  • Pathology (1421)
  • Pharmacology and Toxicology (2483)
  • Physiology (3706)
  • Plant Biology (8055)
  • Scientific Communication and Education (1433)
  • Synthetic Biology (2211)
  • Systems Biology (6019)
  • Zoology (1251)