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Unravelling the conformational dynamics of pathogenic mutations of apolipoprotein M: an integrative computational and

Rahul Yadav1, Krishnan Venkatraman1

  • 1Centre for Bio-Separation Technology (CBST), Vellore Institute of Technology (VIT), Vellore, India.

Journal of Biomolecular Structure & Dynamics
|June 16, 2026
PubMed

Insights

Apolipoprotein M (ApoM) mutations impact its structure and function, potentially affecting high-density lipoprotein (HDL) roles in cardiovascular health. This study identifies specific harmful ApoM variants and their structural consequences.

Area of Science:

  • Biochemistry
  • Structural Biology
  • Genetics

Background:

  • Apolipoprotein M (ApoM) binds sphingosine-1-phosphate (S1P) and is crucial for high-density lipoprotein (HDL) function, reverse cholesterol transport, and vascular homeostasis.
  • Dysregulation of ApoM and S1P metabolism is linked to cardiovascular, metabolic, and inflammatory diseases.
  • Understanding ApoM's structural dynamics and the impact of genetic variations is vital.

Purpose of the Study:

  • To systematically investigate the structural and functional consequences of non-synonymous single-nucleotide polymorphisms (nsSNPs) in Apolipoprotein M (ApoM).
  • To identify specific nsSNPs that significantly alter ApoM structure, stability, and predicted function.
  • To provide a framework for prioritizing functionally relevant ApoM mutations.

Main Methods:

  • Utilized an integrated in silico approach to analyze variants within the ApoM protein.
  • Prioritized 162 nsSNPs from an initial set of 4097 variants based on predicted impact.
  • Performed detailed structural analysis of prioritized nsSNPs, including effects on protein core, stability, and binding pocket.

Main Results:

  • Identified A51S, F63V, and R89S as highly deleterious nsSNPs.
  • A51S disrupts the hydrophobic core, leading to a more compact and less flexible structure.
  • F63V causes destabilization by altering beta-turn integrity and binding pocket, increasing solvent exposure.
  • R89S enhances hydrogen bonding, promoting a more stable conformation.
  • Predicted effects of these mutations on S1P binding and HDL functionality.

Conclusions:

  • Specific nsSNPs in ApoM can profoundly impact its structural integrity and dynamics.
  • These structural changes are predicted to influence ApoM's role in S1P binding and HDL-mediated functions.
  • The study provides mechanistic insights into ApoM variant-induced dysfunction and a method for prioritizing mutations.
Keywords:
Apolipoprotein M (ApoM)reverse cholesterol transportsingle nucleotide polymorphism (SNP)sphingosine-1-phosphatevariant

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