Proline/sidechain C-H/O interactions stabilize cis-proline
Harrison C Oven1, Himal K Ganguly1, Neal J Zondlo1
1Department of Chemistry and Biochemistry, University of Delaware, Newark, DE 19716, USA. zondlo@udel.edu.
Physical Chemistry Chemical Physics : PCCP
|February 2, 2026
Summary
C-H/O interactions stabilize cis-proline conformations in proteins, particularly at Glu-Pro sequences. These interactions are also crucial for phosphoserine-proline and phosphothreonine-proline residues.
Area of Science:
- Biochemistry
- Structural Biology
- Computational Chemistry
Background:
- The cis-proline conformation is crucial for protein structure and function.
- Understanding the factors stabilizing cis-proline is essential for protein engineering and drug design.
Purpose of the Study:
- To identify local protein structures that stabilize the cis-proline conformation.
- To investigate the role of C-H/O interactions in stabilizing cis-proline.
Main Methods:
- Bioinformatics analysis of protein data bank (PDB) structures.
- Density Functional Theory (DFT) calculations.
Main Results:
- C-H/O interactions were identified between sidechain oxygen and Pro C-Hα in cis-proline conformations.
- These interactions are most stabilizing in Glu-Pro sequences, showing a high frequency of cis-proline.
- DFT calculations confirmed the stabilizing role of C-H/O interactions, especially with anionic residues like Glu and Asp.
- C-H/O interactions also stabilize cis-proline at phosphoserine-proline and phosphothreonine-proline, with stronger interactions in their dianionic forms.
Conclusions:
- C-H/O interactions are a key stabilizing factor for cis-proline conformations.
- The findings explain the higher activation barrier for amide bond isomerism in phosphoserine-proline and phosphothreonine-proline sequences.
- These interactions may also stabilize other cis amide bonds, highlighting their functional importance.
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