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Molecular dynamics simulations and structural bioinformatics of bacterial integral alpha-helical membrane enzymes and their AlphaFold2-predicted water-soluble QTY analogues.

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Title: Molecular dynamics simulations and structural bioinformatics of bacterial integral alpha-helical membrane enzymes and their AlphaFold2-predicted water-soluble QTY analogues.
Authors: Sajeev-Sheeja, Akash1 (AUTHOR), Karagöl, Alper2 (AUTHOR), Karagöl, Taner2 (AUTHOR), Zhang, Shuguang3 (AUTHOR) Shuguang@media.mit.edu
Source: Molecular Simulation. Oct2025, Vol. 51 Issue 15, p984-998. 15p.
Subjects: Molecular dynamics, Structural bioinformatics, Enzyme stability, Protein engineering, Membrane proteins, Protein structure prediction, Solubility
Abstract: The study of integral membrane proteins has long been challenging because of their poor solubility in aqueous environments. We previously used QTY code to enhance the hydrophilicity in alpha-helices, beta-barrels, and monoclonal antibodies by systematically pairwise replacing the hydrophobic amino acids L (leucine) to Q (glutamine), V(valine)/I(isoleucine) to T (threonine), and F (phenylalanine) to Y (tyrosine). The superposed AlphaFold2-predicted structures of alpha-helical transmembrane enzyme variants with >41% amino acid substitutions displayed remarkable similarity to native structures (RMSD 0.3Å-0.7 Å). We conducted molecular dynamics (MD) simulations, which revealed that, even in the absence of a lipid bilayer, the QTY-modified enzymes retained stable dynamics comparable to their membrane-bound forms. Root mean square fluctuation (RMSF) values remained below 2 Å across the transmembrane and core regions, and residue-wise root mean square deviation (RMSD) values were minimal (<3 Å), indicating that the structural integrity of the protein core was largely preserved. These results suggest that the QTY variants, designed for soluble environments, effectively mimic the stability and conformational rigidity of natural membrane-bound enzymes. Our findings show that the QTY code is a simple method for designing water-soluble membrane protein enzymes in different biological scenarios, and it may encourage further experiments to validate our structural bioinformatics research. [ABSTRACT FROM AUTHOR]
Copyright of Molecular Simulation is the property of Taylor & Francis Ltd and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
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DbLabel: Engineering Source
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  Data: Molecular dynamics simulations and structural bioinformatics of bacterial integral alpha-helical membrane enzymes and their AlphaFold2-predicted water-soluble QTY analogues.
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  Data: &lt;searchLink fieldCode=&quot;JN&quot; term=&quot;%22Molecular+Simulation%22&quot;&gt;Molecular Simulation&lt;/searchLink&gt;. Oct2025, Vol. 51 Issue 15, p984-998. 15p.
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  Data: The study of integral membrane proteins has long been challenging because of their poor solubility in aqueous environments. We previously used QTY code to enhance the hydrophilicity in alpha-helices, beta-barrels, and monoclonal antibodies by systematically pairwise replacing the hydrophobic amino acids L (leucine) to Q (glutamine), V(valine)/I(isoleucine) to T (threonine), and F (phenylalanine) to Y (tyrosine). The superposed AlphaFold2-predicted structures of alpha-helical transmembrane enzyme variants with &gt;41% amino acid substitutions displayed remarkable similarity to native structures (RMSD 0.3&#197;-0.7 &#197;). We conducted molecular dynamics (MD) simulations, which revealed that, even in the absence of a lipid bilayer, the QTY-modified enzymes retained stable dynamics comparable to their membrane-bound forms. Root mean square fluctuation (RMSF) values remained below 2 &#197; across the transmembrane and core regions, and residue-wise root mean square deviation (RMSD) values were minimal (&lt;3 &#197;), indicating that the structural integrity of the protein core was largely preserved. These results suggest that the QTY variants, designed for soluble environments, effectively mimic the stability and conformational rigidity of natural membrane-bound enzymes. Our findings show that the QTY code is a simple method for designing water-soluble membrane protein enzymes in different biological scenarios, and it may encourage further experiments to validate our structural bioinformatics research. [ABSTRACT FROM AUTHOR]
– Name: AbstractSuppliedCopyright
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  Data: &lt;i&gt;Copyright of Molecular Simulation is the property of Taylor &amp; Francis Ltd and its content may not be copied or emailed to multiple sites without the copyright holder&#39;s express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract.&lt;/i&gt; (Copyright applies to all Abstracts.)
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RecordInfo BibRecord:
  BibEntity:
    Identifiers:
      – Type: doi
        Value: 10.1080/08927022.2025.2562932
    Languages:
      – Code: eng
        Text: English
    PhysicalDescription:
      Pagination:
        PageCount: 15
        StartPage: 984
    Subjects:
      – SubjectFull: Molecular dynamics
        Type: general
      – SubjectFull: Structural bioinformatics
        Type: general
      – SubjectFull: Enzyme stability
        Type: general
      – SubjectFull: Protein engineering
        Type: general
      – SubjectFull: Membrane proteins
        Type: general
      – SubjectFull: Protein structure prediction
        Type: general
      – SubjectFull: Solubility
        Type: general
    Titles:
      – TitleFull: Molecular dynamics simulations and structural bioinformatics of bacterial integral alpha-helical membrane enzymes and their AlphaFold2-predicted water-soluble QTY analogues.
        Type: main
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          Name:
            NameFull: Sajeev-Sheeja, Akash
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            NameFull: Karagöl, Alper
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            NameFull: Karagöl, Taner
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            NameFull: Zhang, Shuguang
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          Dates:
            – D: 01
              M: 10
              Text: Oct2025
              Type: published
              Y: 2025
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              Value: 08927022
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              Value: 51
            – Type: issue
              Value: 15
          Titles:
            – TitleFull: Molecular Simulation
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