Molecular dynamics simulation of the follicle-stimulating hormone receptor. Understanding the conformational dynamics of receptor variants at positions N680 and D408 from in silico analysis

PLoS One. 2018 Nov 21;13(11):e0207526. doi: 10.1371/journal.pone.0207526. eCollection 2018.


Follicle-stimulating hormone receptor (FSHR) is a G-protein coupled receptor (GPCR) and a prototype of the glycoprotein hormone receptors subfamily of GPCRs. Structural data of the FSHR ectodomain in complex with follicle-stimulating hormone suggests a "pull and lift" activation mechanism that triggers a conformational change on the seven α-helix transmembrane domain (TMD). To analyze the conformational changes of the FSHR TMD resulting from sequence variants associated with reproductive impairment in humans, we set up a computational approach combining helix modeling and molecular simulation methods to generate conformational ensembles of the receptor at room (300 K) and physiological (310 K) temperatures. We examined the receptor dynamics in an explicit membrane environment of polyunsaturated phospholipids and solvent water molecules. The analysis of the conformational dynamics of the functional (N680 and S680) and dysfunctional (mutations at D408) variants of the FSHR allowed us to validate the FSHR-TMD model. Functional variants display a concerted motion of flexible intracellular regions at TMD helices 5 and 6. Disruption of side chain interactions and conformational dynamics were detected upon mutation at D408 when replaced with alanine, arginine, or tyrosine. Dynamical network analysis confirmed that TMD helices 2 and 5 may share communication pathways in the functional FSHR variants, whereas no connectivity was detected in the dysfunctional mutants, indicating that the global dynamics of the FSHR was sensitive to mutations at amino acid residue 408, a key position apparently linked to misfolding and variable cell surface plasma membrane expression of FSHRs with distinct mutations at this position.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alanine / chemistry
  • Alanine / genetics
  • Amino Acid Sequence / genetics
  • Amino Acids / chemistry*
  • Amino Acids / genetics
  • Computer Simulation
  • Follicle Stimulating Hormone / chemistry*
  • Follicle Stimulating Hormone / genetics
  • Humans
  • Lipid Bilayers / chemistry
  • Lipids / chemistry
  • Lipids / genetics
  • Molecular Conformation*
  • Molecular Dynamics Simulation
  • Point Mutation
  • Protein Conformation, alpha-Helical
  • Protein Folding
  • Receptors, FSH / chemistry*
  • Receptors, FSH / genetics
  • Signal Transduction


  • Amino Acids
  • Lipid Bilayers
  • Lipids
  • Receptors, FSH
  • Follicle Stimulating Hormone
  • Alanine

Grant support

This work was supported by Consejo Mexiquense de Ciencia y Tecnologia ( grant 203G11000/103/2017 to E.J.-V. Consejo Nacional de Ciencia y Tecnologia ( grant 240619 to A.U.-A. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.