madman
Super Moderator
Complex allosteric mechanism!
* The transport of sex steroid hormones in the plasma is largely mediated by sex-hormone binding globulin (SHBG). SHBG is a functional homodimer, meaning it can bind two sex hormones with similar affinities. This binding occurs through a complex allosteric mechanism. This globulin plays a pivotal role in regulating the availability of sex hormones within target tissues and cells.
* The analysis of representative conformations of the highest and lowest interaction energies revealed a high degree of similarity in the binding sites. The SHBG::TES interaction, for which structural data are lacking, exhibited a high degree of structural and energetic similarity to the SHBG::EST and SHBG: DHT complexes. Quantum mechanics calculations demonstrated the following order of theoretical binding affinity, from the highest to lowest: SHBG: DHT > SHBG::EST > SHBG::TES. Furthermore, SER42, PHE67, MET107, and MET139 exhibited the lowest interaction energies, thereby emphasizing the critical role of these residues in SHBG coupling and steroid hormone transport.
* Crystallography revealed that SHBG is a calcium/zinc-binding homodimeric protein capable of carrying two sex hormones concomitantly, one in each monomer (Fig. 1A), through identical high-affinity steroid-binding sites [7]. Although these binding sites are identical, some evidence supports a model involving differences in binding affinity and a multistep occupation process based on allostery [15].
* Our findings confirm the reliability of molecular docking in reproducing experimentally validated binding poses, particularly for DHT and EST. Despite similar conformational behavior across the complexes during molecular dynamics simulations, interaction energies revealed that SHBG has a stronger theoretical affinity for DHT, followed by EST and TES. This ranking aligns with prior experimental observations and highlights the limitations of conventional docking scores for accurately predicting binding affinity. Moreover, these results emphasize the utility of quantum mechanical calculations in understanding binding affinities beyond the capabilities of classical docking scoring functions. Furthermore, our quantum energy decomposition analysis identified key residues, such as SER42, MET107, MET139, and PHE67, as critical contributors to hormone recognition, in a good agreement previous biochemical and computational reports. Notably, this work reports for the first time the molecular interaction profile of SHBG::TES, revealing close similarity to SHBG::EST and SHBG: DHT, which may indicate a conserved mode of recognition for diverse steroid hormones.
Fig. 1. Structures of sex hormone binding globulin (SHBG) and selected hormones. (A) Previously determined global structure of the SHBG monomer. Chemical structures of (B) estradiol (EST), (C) dihydrotestosterone (DHT), and (D) testosterone (TES).
Abstract
The transport of sex steroid hormones in the plasma is largely mediated by sex-hormone binding globulin (SHBG). SHBG is a functional homodimer, meaning it can bind two sex hormones with similar affinities. This binding occurs through a complex allosteric mechanism. This globulin plays a pivotal role in regulating the availability of sex hormones within target tissues and cells. Given the established correlation between SHBG and various pathological disorders, there has been increasing interest in characterizing the interactions between SHBG and hormones as well as in identifying potential inhibitors or modulators of the SHBG function. In this regard, the present study aims to provide novel insights into the binding of SHBG with estradiol (EST), dihydrotestosterone (DHT), and testosterone (TES). To this end, molecular docking, molecular dynamics, and quantum mechanics were employed here. The analysis of representative conformations of the highest and lowest interaction energies revealed a high degree of similarity in the binding sites. The SHBG::TES interaction, for which structural data are lacking, exhibited a high degree of structural and energetic similarity to the SHBG::EST and SHBG: DHT complexes. Quantum mechanics calculations demonstrated the following order of theoretical binding affinity, from the highest to lowest: SHBG: DHT > SHBG::EST > SHBG::TES. Furthermore, SER42, PHE67, MET107, and MET139 exhibited the lowest interaction energies, thereby emphasizing the critical role of these residues in SHBG coupling and steroid hormone transport. The energetic description of these complexes contributes to a deeper understanding of steroid hormone transport and provides new insights for targeting SHBG in drug discovery.
Conclusion
This study presents a theoretical investigation into the binding interactions between the SHBG monomer and three major steroid hormones: DHT, EST, and TES. By integrating molecular docking, classical molecular dynamics, and quantum mechanics approaches, we provide insights into the structural and energetic features that govern SHBG::Steroid recognition. Our findings confirm the reliability of molecular docking in reproducing experimentally validated binding poses, particularly for DHT and EST. Despite similar conformational behavior across the complexes during molecular dynamics simulations, interaction energies revealed that SHBG has a stronger theoretical affinity for DHT, followed by EST and TES. This ranking aligns with prior experimental observations and highlights the limitations of conventional docking scores for accurately predicting binding affinity. Moreover, these results emphasize the utility of quantum mechanical calculations in understanding binding affinities beyond the capabilities of classical docking scoring functions. Furthermore, our quantum energy decomposition analysis identified key residues, such as SER42, MET107, MET139, and PHE67, as critical contributors to hormone recognition, in a good agreement previous biochemical and computational reports. Notably, this work reports for the first time the molecular interaction profile of SHBG::TES, revealing close similarity to SHBG::EST and SHBG: DHT, which may indicate a conserved mode of recognition for diverse steroid hormones. The findings of this study may be useful for future structure-based drug design efforts aimed at modulating SHBG function or developing inhibitors to regulate steroid hormone availability.
* The transport of sex steroid hormones in the plasma is largely mediated by sex-hormone binding globulin (SHBG). SHBG is a functional homodimer, meaning it can bind two sex hormones with similar affinities. This binding occurs through a complex allosteric mechanism. This globulin plays a pivotal role in regulating the availability of sex hormones within target tissues and cells.
* The analysis of representative conformations of the highest and lowest interaction energies revealed a high degree of similarity in the binding sites. The SHBG::TES interaction, for which structural data are lacking, exhibited a high degree of structural and energetic similarity to the SHBG::EST and SHBG: DHT complexes. Quantum mechanics calculations demonstrated the following order of theoretical binding affinity, from the highest to lowest: SHBG: DHT > SHBG::EST > SHBG::TES. Furthermore, SER42, PHE67, MET107, and MET139 exhibited the lowest interaction energies, thereby emphasizing the critical role of these residues in SHBG coupling and steroid hormone transport.
* Crystallography revealed that SHBG is a calcium/zinc-binding homodimeric protein capable of carrying two sex hormones concomitantly, one in each monomer (Fig. 1A), through identical high-affinity steroid-binding sites [7]. Although these binding sites are identical, some evidence supports a model involving differences in binding affinity and a multistep occupation process based on allostery [15].
* Our findings confirm the reliability of molecular docking in reproducing experimentally validated binding poses, particularly for DHT and EST. Despite similar conformational behavior across the complexes during molecular dynamics simulations, interaction energies revealed that SHBG has a stronger theoretical affinity for DHT, followed by EST and TES. This ranking aligns with prior experimental observations and highlights the limitations of conventional docking scores for accurately predicting binding affinity. Moreover, these results emphasize the utility of quantum mechanical calculations in understanding binding affinities beyond the capabilities of classical docking scoring functions. Furthermore, our quantum energy decomposition analysis identified key residues, such as SER42, MET107, MET139, and PHE67, as critical contributors to hormone recognition, in a good agreement previous biochemical and computational reports. Notably, this work reports for the first time the molecular interaction profile of SHBG::TES, revealing close similarity to SHBG::EST and SHBG: DHT, which may indicate a conserved mode of recognition for diverse steroid hormones.
Fig. 1. Structures of sex hormone binding globulin (SHBG) and selected hormones. (A) Previously determined global structure of the SHBG monomer. Chemical structures of (B) estradiol (EST), (C) dihydrotestosterone (DHT), and (D) testosterone (TES).
Abstract
The transport of sex steroid hormones in the plasma is largely mediated by sex-hormone binding globulin (SHBG). SHBG is a functional homodimer, meaning it can bind two sex hormones with similar affinities. This binding occurs through a complex allosteric mechanism. This globulin plays a pivotal role in regulating the availability of sex hormones within target tissues and cells. Given the established correlation between SHBG and various pathological disorders, there has been increasing interest in characterizing the interactions between SHBG and hormones as well as in identifying potential inhibitors or modulators of the SHBG function. In this regard, the present study aims to provide novel insights into the binding of SHBG with estradiol (EST), dihydrotestosterone (DHT), and testosterone (TES). To this end, molecular docking, molecular dynamics, and quantum mechanics were employed here. The analysis of representative conformations of the highest and lowest interaction energies revealed a high degree of similarity in the binding sites. The SHBG::TES interaction, for which structural data are lacking, exhibited a high degree of structural and energetic similarity to the SHBG::EST and SHBG: DHT complexes. Quantum mechanics calculations demonstrated the following order of theoretical binding affinity, from the highest to lowest: SHBG: DHT > SHBG::EST > SHBG::TES. Furthermore, SER42, PHE67, MET107, and MET139 exhibited the lowest interaction energies, thereby emphasizing the critical role of these residues in SHBG coupling and steroid hormone transport. The energetic description of these complexes contributes to a deeper understanding of steroid hormone transport and provides new insights for targeting SHBG in drug discovery.
Conclusion
This study presents a theoretical investigation into the binding interactions between the SHBG monomer and three major steroid hormones: DHT, EST, and TES. By integrating molecular docking, classical molecular dynamics, and quantum mechanics approaches, we provide insights into the structural and energetic features that govern SHBG::Steroid recognition. Our findings confirm the reliability of molecular docking in reproducing experimentally validated binding poses, particularly for DHT and EST. Despite similar conformational behavior across the complexes during molecular dynamics simulations, interaction energies revealed that SHBG has a stronger theoretical affinity for DHT, followed by EST and TES. This ranking aligns with prior experimental observations and highlights the limitations of conventional docking scores for accurately predicting binding affinity. Moreover, these results emphasize the utility of quantum mechanical calculations in understanding binding affinities beyond the capabilities of classical docking scoring functions. Furthermore, our quantum energy decomposition analysis identified key residues, such as SER42, MET107, MET139, and PHE67, as critical contributors to hormone recognition, in a good agreement previous biochemical and computational reports. Notably, this work reports for the first time the molecular interaction profile of SHBG::TES, revealing close similarity to SHBG::EST and SHBG: DHT, which may indicate a conserved mode of recognition for diverse steroid hormones. The findings of this study may be useful for future structure-based drug design efforts aimed at modulating SHBG function or developing inhibitors to regulate steroid hormone availability.
