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Abstract
Functionally required conformational plasticity of transmembrane proteins implies
that specific structural motifs have been integrated in transmembrane helices. Surveying
a database of transmembrane helices and the large family of G-protein coupled receptors
we identified a series of overrepresented motifs associating Pro with either Ser or
Thr. Thus, we have studied the conformation of Pro-kinked transmembrane helices containing
Ser or Thr residues, in both g+ and g- rotamers, by molecular dynamics simulations
in a hydrophobic environment. Analysis of the simulations shows that Ser or Thr can
significantly modulate the deformation of the Pro. A series of motifs, such as (S/T)P
and (S/T)AP in the g+ rotamer and the TAP and PAA(S/T) motifs in the g- rotamer, induce
an increase in bending angle of the helix compared to a standard Pro-kink, apparently
due to the additional hydrogen bond formed between the side chain of Ser/Thr and the
backbone carbonyl oxygen. In contrast, (S/T)AAP and PA(S/T) motifs, in both g+ and
g-, and PAA(S/T) in g+ rotamers decrease the bending angle of the helix by either
reducing the steric clash between the pyrrolidine ring of Pro and the helical backbone,
or by adding a constrain in the form of a hydrogen bond in the curved-in face of the
helix. Together with a number of available experimental data, our results strongly
suggest that association of Ser and Thr with Pro is commonly used in transmembrane
helices to accommodate the structural needs of specific functions.