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<p>Monoamine oxidase A (MAO-A) is a key enzyme responsible for serotonin degradation and mutations in the <i>MAOA</i> gene are associated with impaired enzymatic function and neuropsychiatric disorders, including Brunner syndrome. Although previous studies have demonstrated that such mutations reduce catalytic efficiency, their effects on substrate binding remain poorly understood. Here, we employed an integrated computational approach combining molecular docking, molecular dynamics simulations, and MM-GBSA binding free energy calculations to investigate the impact of four clinically relevant MAO-A variants (C266F, V244I, E446K, and R45W) on serotonin binding and active-site stability. Using a one-substrate, multiple-variant framework, we systematically compared disease-associated MAO-A variants and identified both shared and mutation-specific mechanisms affecting ligand recognition. All investigated mutants exhibited reduced serotonin binding affinity relative to the wild-type enzyme, as reflected by positive ΔΔ<i>G</i> values. Structural and energetic analyses revealed that this loss of affinity does not arise from major conformational changes but from mutation-induced perturbations of protein dynamics. Increased flexibility of second-shell residues promoted enhanced breathing of the binding pocket, leading to greater solvent-accessible surface area and increased water penetration into the active site. Consequently, the hydrophobic environment required for efficient substrate stabilization was compromised, weakening key hydrogen-bonding and electrostatic interactions. Residue-level energy decomposition identified unfavorable electrostatic contributions involving the FAD cofactor and active-site residues such as Tyr444 and Gln215 as major determinants of reduced binding affinity. Overall, our results demonstrate that mutation-induced changes in protein dynamics, hydration, and electrostatics collectively impair serotonin binding in MAO-A, providing molecular-level insight into the functional consequences of Brunner syndrome-associated mutations.</p>

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Elucidating the molecular basis of Brunner syndrome: how clinically relevant mutations disrupt serotonin binding and active-site stability in monoamine oxidase A

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年8月5日

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  • Martina Rajić,
  • Jernej Stare,
  • Lucija Vrban Đerek,
  • Marija Sollner Dolenc,
  • Janez Mavri,
  • Robert Vianello

摘要

Monoamine oxidase A (MAO-A) is a key enzyme responsible for serotonin degradation and mutations in the MAOA gene are associated with impaired enzymatic function and neuropsychiatric disorders, including Brunner syndrome. Although previous studies have demonstrated that such mutations reduce catalytic efficiency, their effects on substrate binding remain poorly understood. Here, we employed an integrated computational approach combining molecular docking, molecular dynamics simulations, and MM-GBSA binding free energy calculations to investigate the impact of four clinically relevant MAO-A variants (C266F, V244I, E446K, and R45W) on serotonin binding and active-site stability. Using a one-substrate, multiple-variant framework, we systematically compared disease-associated MAO-A variants and identified both shared and mutation-specific mechanisms affecting ligand recognition. All investigated mutants exhibited reduced serotonin binding affinity relative to the wild-type enzyme, as reflected by positive ΔΔG values. Structural and energetic analyses revealed that this loss of affinity does not arise from major conformational changes but from mutation-induced perturbations of protein dynamics. Increased flexibility of second-shell residues promoted enhanced breathing of the binding pocket, leading to greater solvent-accessible surface area and increased water penetration into the active site. Consequently, the hydrophobic environment required for efficient substrate stabilization was compromised, weakening key hydrogen-bonding and electrostatic interactions. Residue-level energy decomposition identified unfavorable electrostatic contributions involving the FAD cofactor and active-site residues such as Tyr444 and Gln215 as major determinants of reduced binding affinity. Overall, our results demonstrate that mutation-induced changes in protein dynamics, hydration, and electrostatics collectively impair serotonin binding in MAO-A, providing molecular-level insight into the functional consequences of Brunner syndrome-associated mutations.