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<p>The rising surge of prostate cancer (PC) and its evolution to metastatic castration resistant prostate cancer (mCRPC) all around the globe, calls for a brisk treatment target characterization. Androgen receptor (AR) is a well-proclaimed mCRPC driver, identified in various mutant forms in PC samples. The mutation of a conserved cysteine in the DNA binding domain (DBD) of AR (C620Y) has been known to cause receptor inactivation with attenuated DNA binding. In our study, we dug into the root of destabilization of wild type AR DBD (WT_AR) owing to mutation C620Y_AR, at unbound and bound levels utilizing a detailed parametric normal mode simulation. An unsettling root mean square deviation curve hinted at the loss of conformational stability upon mutation. Radius of gyration and solvent exposure also described a more perpetuating stability in WT_AR. Intramolecular forces of hydrogen bond count affected the secondary structural network of the terminal residues of C620Y_AR during the second half of the simulation while inconsistent hydrophobic interactions implied varied hydrophobicity clusters on protein surfaces. Root mean square fluctuation reflected the hike in residual flexibility and altered residual cross-correlation network especially, at DNA-binding sites which caused the binding site to shift beyond K581-R586 to K591-K610. Principal component analysis symbolized WT_AR conformational homogeneity, with kinetically microstable states. Concomitantly, a disrupted nucleotide pattern recognition, imbalanced loss of local solvent accessibility and altered electrostatic charge distribution was observed in C620Y. The description provided in this study presents a comprehensive cause-and-effect relationship between mutational inactivation, reduced DNA-binding affinity and PC progression.</p>

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C620Y Mutation–Induced Destabilization of the Androgen Receptor Disrupts DNA Recognition Specificity in Prostate Cancer: Insights from Extensive Parametric Normal Mode Simulations

  • 期刊论文

  • 发表日期：

    2026年3月7日

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  • Ishani Paul,
  • Sujay Ray

摘要

The rising surge of prostate cancer (PC) and its evolution to metastatic castration resistant prostate cancer (mCRPC) all around the globe, calls for a brisk treatment target characterization. Androgen receptor (AR) is a well-proclaimed mCRPC driver, identified in various mutant forms in PC samples. The mutation of a conserved cysteine in the DNA binding domain (DBD) of AR (C620Y) has been known to cause receptor inactivation with attenuated DNA binding. In our study, we dug into the root of destabilization of wild type AR DBD (WT_AR) owing to mutation C620Y_AR, at unbound and bound levels utilizing a detailed parametric normal mode simulation. An unsettling root mean square deviation curve hinted at the loss of conformational stability upon mutation. Radius of gyration and solvent exposure also described a more perpetuating stability in WT_AR. Intramolecular forces of hydrogen bond count affected the secondary structural network of the terminal residues of C620Y_AR during the second half of the simulation while inconsistent hydrophobic interactions implied varied hydrophobicity clusters on protein surfaces. Root mean square fluctuation reflected the hike in residual flexibility and altered residual cross-correlation network especially, at DNA-binding sites which caused the binding site to shift beyond K581-R586 to K591-K610. Principal component analysis symbolized WT_AR conformational homogeneity, with kinetically microstable states. Concomitantly, a disrupted nucleotide pattern recognition, imbalanced loss of local solvent accessibility and altered electrostatic charge distribution was observed in C620Y. The description provided in this study presents a comprehensive cause-and-effect relationship between mutational inactivation, reduced DNA-binding affinity and PC progression.