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Transmembrane helix association affinity can be modulated by flanking and noninterfacial residues

Jinming Zhang1, Themis Lazaridis

  • 1Department of Chemistry, City College of New York/CUNY, New York, NY 10031, USA.

Biophysical Journal
|June 3, 2009
PubMed

Insights

The GxxxG motif is crucial for transmembrane helix association, but not sufficient for strong binding. Molecular dynamics simulations reveal that flanking residues and specific residue positioning significantly influence helix association affinity, explaining experimental differences between proteins like glycophorin A and M13 major coat protein.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Computational Biology

Background:

  • Transmembrane (TM) helices associate via specific sequence motifs, such as GxxxG.
  • The GxxxG motif alone is insufficient to determine strong helix association affinity.
  • Experimental data show varying association strengths for proteins with GxxxG motifs, like glycophorin A (GpA) and M13 major coat protein (MCP).

Purpose of the Study:

  • To explain the experimentally observed differences in TM helix association affinity between GpA and MCP.
  • To investigate the role of the GxxxG motif and flanking residues in TM helix association.
  • To elucidate the molecular mechanisms underlying TM helix dimerization using computational simulations.

Main Methods:

  • Molecular dynamics simulations in an implicit membrane (IMM1-GC) environment.
  • Calculation and comparison of association free energies for different TM helix constructs (GpA29, GpA15p11, MCP, MCP-GpA).
  • Analysis of the structural and energetic contributions of interfacial and non-interfacial residues, including Lys-40 deprotonation.

Main Results:

  • Calculated association free energies align with experimental observations, showing MCP-GpA affinity between GpA15p11 and wild-type MCP.
  • Identified burial of non-interfacial Lys-40 in the MCP dimer as a key factor weakening association, leading to its deprotonation.
  • Demonstrated that flanking residues significantly enhance association affinity (GpA15p11 vs. GpA29) and their positioning is critical.

Conclusions:

  • TM helix association affinity is modulated by factors beyond the GxxxG motif, including flanking residues and their precise positioning.
  • Non-interfacial residues can significantly impact helix association by influencing stability and energetics.
  • Computational simulations provide a mechanistic explanation for experimental findings on TM helix dimerization.

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