also sometimes evident in secondary structure. For example, consecutive residues and residues offset by 4 in the primary sequence often interact in α helices. Also, residues offset by 2 in the primary sequence point their sidechains toward the same face of β sheets and are close enough to interact sterically, as are residues on adjacent strands of the same β sheet. Some of these conformational changes are induced by post-translational modifications in protein structure, such as phosphorylation and methylation. When these coupled residues form pathways linking functionally important parts of a protein, they may participate in allosteric signaling. For example, when a molecule of oxygen binds to one subunit of the hemoglobin tetramer, that information is allosterically propagated to the other three subunits, thereby enhancing their affinity for oxygen. In this case, the coupled flexibility in hemoglobin allows for cooperative oxygen binding, which is physiologically useful because it allows rapid oxygen loading in lung tissue and rapid oxygen unloading in oxygen-deprived tissues (e.g. muscle). Global flexibility: multiple domains The presence of multiple domains in proteins gives rise to a great deal of flexibility and mobility, leading to protein domain dynamics. Domain motions can be inferred by comparing different structures of a protein (as in Database of Molecular Motions), or they can be directly observed using spectra measured by neutron spin echo spectroscopy. They can also be suggested by sampling in extensive molecular dynamics trajectories and principal component analysis. Domain motions are important for: ABC transporters catalysis cellular locomotion and motor proteins formation of protein complexes ion channels mechanoreceptors and mechanotransduction regulatory activity transport of metabolites across cell membranes One of the largest observed domain motions is the 'swivelling' mechanism in pyruvate phosphate dikinase. The phosphoinositide domain swivels between two states in order to bring a phosphate group from the active site of the nucleotide binding domain to that of the phosphoenolpyruvate/pyruvate domain. The phosphate group is moved over a distance of 45 Å involving a domain motion of about 100 degrees around a single residue. In enzymes, the closure of one domain onto another captures a substrate by an induced fit, allowing the reaction to take place in a controlled way. A detailed analysis by Gerstein led to the classification of two basic types of domain motion; hinge and shear. Only a relatively small portion of the chain, namely the inter-domain linker and side chains undergo significant conformational changes upon