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Glycosylation Effects on FSH-FSHR Interaction Dynamics: A Case Study of Different FSH Glycoforms by Molecular Dynamics Simulations.

Meher BR, Dixit A, Bousfield GR, Lushington GH - PLoS ONE (2015)

Bottom Line: However, substantial qualitative differences emerge between FSH15 and FSH24 when FSH is decorated with a much larger, tetra-antennary glycan.Specifically, the FSHR complex with hypo-glycosylated FSH15 is observed to undergo a significant conformational shift after 5-10 ns of simulation, indicating that FSH15 has greater conformational flexibility than FSH24 which may explain the more favorable FSH15 kinetic profile.FSH15 also exhibits a stronger binding free energy, due in large part to formation of closer and more persistent salt-bridges with FSHR.

View Article: PubMed Central - PubMed

Affiliation: Bioinformatics Core Facility, University of Kansas, Lawrence, Kansas, United States of America.

ABSTRACT
The gonadotropin known as follicle-stimulating hormone (FSH) plays a key role in regulating reproductive processes. Physiologically active FSH is a glycoprotein that can accommodate glycans on up to four asparagine residues, including two sites in the FSHα subunit that are critical for biochemical function, plus two sites in the β subunit, whose differential glycosylation states appear to correspond to physiologically distinct functions. Some degree of FSHβ hypo-glycosylation seems to confer advantages toward reproductive fertility of child-bearing females. In order to identify possible mechanistic underpinnings for this physiological difference we have pursued computationally intensive molecular dynamics simulations on complexes between the high affinity site of the gonadal FSH receptor (FSHR) and several FSH glycoforms including fully-glycosylated (FSH24), hypo-glycosylated (e.g., FSH15), and completely deglycosylated FSH (dgFSH). These simulations suggest that deviations in FSH/FSHR binding profile as a function of glycosylation state are modest when FSH is adorned with only small glycans, such as single N-acetylglucosamine residues. However, substantial qualitative differences emerge between FSH15 and FSH24 when FSH is decorated with a much larger, tetra-antennary glycan. Specifically, the FSHR complex with hypo-glycosylated FSH15 is observed to undergo a significant conformational shift after 5-10 ns of simulation, indicating that FSH15 has greater conformational flexibility than FSH24 which may explain the more favorable FSH15 kinetic profile. FSH15 also exhibits a stronger binding free energy, due in large part to formation of closer and more persistent salt-bridges with FSHR.

No MeSH data available.


Energy components (kcal/mol) for the binding of FSH/FSHR in different systems like the dgFSH, FSH15(NAG), FSH24(NAG), FSH15(TAG), and FSH24(TAG): INT: Internal energies arising from bond, angle, and dihedral terms, ELE: Electrostatic energy in the gas phase; VDW: van der Waals energy; GBSOL: sum of polar and non-polar solvation energies; GBTOT: Total binding free energies.Error bars shown in black solid line specifies the difference in terms of standard deviations.
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pone.0137897.g010: Energy components (kcal/mol) for the binding of FSH/FSHR in different systems like the dgFSH, FSH15(NAG), FSH24(NAG), FSH15(TAG), and FSH24(TAG): INT: Internal energies arising from bond, angle, and dihedral terms, ELE: Electrostatic energy in the gas phase; VDW: van der Waals energy; GBSOL: sum of polar and non-polar solvation energies; GBTOT: Total binding free energies.Error bars shown in black solid line specifies the difference in terms of standard deviations.

Mentions: In order to assess the thermodynamic factors underlying differential FSHR binding affinity as a function of FSH glycosylation state, our GBSA calculations reveal that substantial differences arise in the FSH binding free energy for different complexes. Fig 10 and Table 1 reveals that the fully deglycosylated FSH binds with greatest affinity (GBTOT = total GBSA binding free energy) to the cellular FSH receptor. Smaller NAG glycans effect, if anything, only a minimal energetic perturbation to complex stability: the total binding energy for the FSH15 and FSH24 ligands exhibit no real statistical difference relative to the fully deglycosylated protein. With the caveat that differences in the GBSA free energy numbers are below the threshold for statistical significance, one may note that the appearance of a modest possible trend toward decreasing complex stability as a function of greater FSH glycosylation. This trend is substantially magnified for the larger TAG glycans where there is a large and significant decrease in free energy stabilization in comparing the deglycosylated and partially glycosylated states. Among the TAG isoforms, a similarly large difference in binding affinity is predicted in comparing partially- and fully-glycosylated FSH.


Glycosylation Effects on FSH-FSHR Interaction Dynamics: A Case Study of Different FSH Glycoforms by Molecular Dynamics Simulations.

Meher BR, Dixit A, Bousfield GR, Lushington GH - PLoS ONE (2015)

Energy components (kcal/mol) for the binding of FSH/FSHR in different systems like the dgFSH, FSH15(NAG), FSH24(NAG), FSH15(TAG), and FSH24(TAG): INT: Internal energies arising from bond, angle, and dihedral terms, ELE: Electrostatic energy in the gas phase; VDW: van der Waals energy; GBSOL: sum of polar and non-polar solvation energies; GBTOT: Total binding free energies.Error bars shown in black solid line specifies the difference in terms of standard deviations.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4581761&req=5

pone.0137897.g010: Energy components (kcal/mol) for the binding of FSH/FSHR in different systems like the dgFSH, FSH15(NAG), FSH24(NAG), FSH15(TAG), and FSH24(TAG): INT: Internal energies arising from bond, angle, and dihedral terms, ELE: Electrostatic energy in the gas phase; VDW: van der Waals energy; GBSOL: sum of polar and non-polar solvation energies; GBTOT: Total binding free energies.Error bars shown in black solid line specifies the difference in terms of standard deviations.
Mentions: In order to assess the thermodynamic factors underlying differential FSHR binding affinity as a function of FSH glycosylation state, our GBSA calculations reveal that substantial differences arise in the FSH binding free energy for different complexes. Fig 10 and Table 1 reveals that the fully deglycosylated FSH binds with greatest affinity (GBTOT = total GBSA binding free energy) to the cellular FSH receptor. Smaller NAG glycans effect, if anything, only a minimal energetic perturbation to complex stability: the total binding energy for the FSH15 and FSH24 ligands exhibit no real statistical difference relative to the fully deglycosylated protein. With the caveat that differences in the GBSA free energy numbers are below the threshold for statistical significance, one may note that the appearance of a modest possible trend toward decreasing complex stability as a function of greater FSH glycosylation. This trend is substantially magnified for the larger TAG glycans where there is a large and significant decrease in free energy stabilization in comparing the deglycosylated and partially glycosylated states. Among the TAG isoforms, a similarly large difference in binding affinity is predicted in comparing partially- and fully-glycosylated FSH.

Bottom Line: However, substantial qualitative differences emerge between FSH15 and FSH24 when FSH is decorated with a much larger, tetra-antennary glycan.Specifically, the FSHR complex with hypo-glycosylated FSH15 is observed to undergo a significant conformational shift after 5-10 ns of simulation, indicating that FSH15 has greater conformational flexibility than FSH24 which may explain the more favorable FSH15 kinetic profile.FSH15 also exhibits a stronger binding free energy, due in large part to formation of closer and more persistent salt-bridges with FSHR.

View Article: PubMed Central - PubMed

Affiliation: Bioinformatics Core Facility, University of Kansas, Lawrence, Kansas, United States of America.

ABSTRACT
The gonadotropin known as follicle-stimulating hormone (FSH) plays a key role in regulating reproductive processes. Physiologically active FSH is a glycoprotein that can accommodate glycans on up to four asparagine residues, including two sites in the FSHα subunit that are critical for biochemical function, plus two sites in the β subunit, whose differential glycosylation states appear to correspond to physiologically distinct functions. Some degree of FSHβ hypo-glycosylation seems to confer advantages toward reproductive fertility of child-bearing females. In order to identify possible mechanistic underpinnings for this physiological difference we have pursued computationally intensive molecular dynamics simulations on complexes between the high affinity site of the gonadal FSH receptor (FSHR) and several FSH glycoforms including fully-glycosylated (FSH24), hypo-glycosylated (e.g., FSH15), and completely deglycosylated FSH (dgFSH). These simulations suggest that deviations in FSH/FSHR binding profile as a function of glycosylation state are modest when FSH is adorned with only small glycans, such as single N-acetylglucosamine residues. However, substantial qualitative differences emerge between FSH15 and FSH24 when FSH is decorated with a much larger, tetra-antennary glycan. Specifically, the FSHR complex with hypo-glycosylated FSH15 is observed to undergo a significant conformational shift after 5-10 ns of simulation, indicating that FSH15 has greater conformational flexibility than FSH24 which may explain the more favorable FSH15 kinetic profile. FSH15 also exhibits a stronger binding free energy, due in large part to formation of closer and more persistent salt-bridges with FSHR.

No MeSH data available.