title: Mutations in herpes simplex virus gD protein affect receptor binding by different molecular mechanisms.
abstract: Glycoprotein D (gD) is an essential protein of herpes simplex virus-1 (HSV-1) that targets the structurally unrelated receptors HVEM and nectin-1. Receptor binding of gD is accompanied by intramolecular structural rearrangements including the detachment of the C-terminus or formation of an N-terminal hairpin structure. We have investigated several gD mutations that were reported to affect receptor binding affinity or specificity in order to identify their molecular mode of action. Molecular dynamics simulations and subsequent energetic analyses of the gD-receptor complexes reveal that some mutations (M11A, N15A, L28A, T29A) play a more prominent role for HVEM binding than for nectin-1 binding, thereby conferring specificity to receptor recognition. However, our studies show that mutations can also affect the intramolecular structural rearrangement processes in gD. W294A and Q27A mutations facilitate the detachment of the C-terminus, and Q27A additionally hampers the formation of an intramolecular hairpin in gD that is exclusively established upon HVEM binding. The finding that a Q27A mutation affects multiple steps of the receptor binding process offers a molecular explanation for its enhanced nectin-1 affinity and the pronounced receptor specificity. This study also indicates that an inspection of the gD-receptor interfaces alone may be insufficient for predicting the effect of novel mutations that alter receptor specificity. Instead, such an analysis will additionally require to assess the effect of candidate mutation on the preceding steps of gD activation.
authors.affiliation: Bioinformatik, Institut für Biochemie, Friedrich-Alexander-Universität Erlangen-Nürnberg, Fahrstraße 17, 91054, Erlangen, Germany.
authors.forename: Joachim D
authors.initials: JD
authors.lastname: Stump
authors.forename: Heinrich
authors.initials: H
authors.lastname: Sticht
mesh_terms: D019943:Amino Acid Substitution; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D009154:Mutation; D011485:Protein Binding; D011487:Protein Conformation; D011991:Receptors, Virus / Q000737:chemistry* / Q000378:metabolism; D014759:Viral Envelope Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism
chemical_list: D011991:Receptors, Virus; D014759:Viral Envelope Proteins; C039447:glycoprotein D, Human herpesvirus 1