ABSTRACT
Plasma membrane lipids significantly affect assembly and activity of many signaling networks. The present work is aimed at analyzing, by molecular dynamics simulations, the structure and dynamics of the CD3 ζζ dimer in palmitoyl-oleoyl-phosphatidylcholine bilayer (POPC) and in POPC/cholesterol/sphingomyelin bilayer, which resembles the raft membrane microdomain supposed to be the site of the signal transducing machinery. Both POPC and raft-like environment produce significant alterations in structure and flexibility of the CD3 ζζ with respect to nuclear magnetic resonance (NMR) model: the dimer is more compact, its secondary structure is slightly less ordered, the arrangement of the Asp6 pair, which is important for binding to the Arg residue in the alpha chain of the T cell receptor (TCR), is stabilized by water molecules. Different interactions of charged residues with lipids at the lipid-cytoplasm boundary occur when the two environments are compared. Furthermore, in contrast to what is observed in POPC, in the raft-like environment correlated motions between transmembrane and cytoplasmic regions are observed. Altogether the data suggest that when the TCR complex resides in the raft domains, the CD3 ζζ dimer assumes a specific conformation probably necessary to the correct signal transduction.
Subject(s)
1,2-Dipalmitoylphosphatidylcholine/analogs & derivatives , CD3 Complex/chemistry , Lipid Bilayers/chemistry , Membrane Microdomains/chemistry , 1,2-Dipalmitoylphosphatidylcholine/chemistry , Amino Acid Sequence , Dimerization , Models, Molecular , Molecular Dynamics Simulation , Molecular Sequence Data , Sequence Homology, Amino AcidABSTRACT
NO binding to the T-state of human hemoglobin (HbA) induces the cleavage of the proximal His bonds to the heme iron in the α-chains, whereas it leaves the ß-hemes hexacoordinated. The structure of the nitrosylated T-state of the W37Eß mutant (W37E) shows that the Fe-His87α bond remains intact. Exactly how mutation affects NO binding and why tension is apparent only in HbA α-heme remains to be elucidated. By means of density functional theory electronic structure calculations and classical molecular dynamics simulations we provide an explanation for the poorly understood NO binding properties of HbA and its W37E mutant. The data suggest an interplay between electronic effects, tertiary structure and hydration site modifications in determining the tension in the NO-ligated T-state HbA α-chain.