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A Self-Consistent Approach to Rotamer and Protonation State Assignments (RAPA): Moving Beyond Single Protein

Mossa Ghattas1, Prerna Gera2, Steven Ramsey3

  • 1Ph.D. Program in Chemistry, The Graduate Center, City University of New York, New York, New York 10016, United States.

Journal of Chemical Information and Modeling
|June 11, 2025
PubMed
Summary
This summary is machine-generated.

Ambiguities in protein crystal structures arise from unresolvable atoms, leading to multiple possible rotamer and protonation states. Our Rotamer and Protonation Assignment (RAPA) protocol identifies these energetically consistent states, revealing multiple configurations for most proteins.

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Area of Science:

  • Structural Biology
  • Computational Biology
  • Biochemistry

Background:

  • Protein Data Bank contains over 160,000 X-ray crystal structures at resolutions where hydrogen atoms are unresolvable.
  • Low-resolution crystal structures lead to ambiguity in rotamer and protonation states of key amino acids (Asn, Gln, His, Ser, Tyr, Thr).
  • Changes in these states alter the binding site's electrochemical surface, impacting molecular interactions.

Purpose of the Study:

  • To address the ambiguity in rotamer and protonation states of amino acid residues in protein crystal structures.
  • To introduce a novel computational protocol, Rotamer and Protonation Assignment (RAPA), for analyzing these states.
  • To determine if multiple energetically consistent states exist and are computationally feasible to investigate.

Main Methods:

  • Developed the Rotamer and Protonation Assignment (RAPA) protocol.
  • RAPA analyzes local hydrogen-bonding environments in resolved protein structures.
  • Evaluated RAPA-predicted configurations using molecular dynamics simulations.

Main Results:

  • Identified a set of unique rotamer and protonation states energetically consistent with experimental crystal structures.
  • Found multiple configurations for most proteins (69/77) that are consistent with X-ray data.
  • The number of accessible states is limited (≤8 for 62/77 proteins), suggesting computational feasibility.

Conclusions:

  • Multiple rotamer and protonation states are consistent with experimentally determined protein crystal structures.
  • The RAPA protocol provides a feasible method to identify these states.
  • This approach avoids a combinatorial explosion, enabling comprehensive analysis of protein binding site electrochemistry.