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The helix–loop–helix (i.e. EF-hand) Ca 2+  ion binding motif is characteristic of a large family of high-affinity Ca 2+  ion binding proteins, including the parvalbumins and calmodulins. In this paper we describe a set of molecular dynamics computations on the major parvalbumin from the silver hake (SHPV-B). In all variants examined, both whole protein and fragments thereof, the ninth loop residue in the Ca 2+  binding coordination site in the CD helix–loop–helix region (the so-called `gateway' residue) has been mutated. The three gateway mutations examined are arginine, which has never been found at the gateway position of any EF-hand protein, cysteine, which is the residue observed least in natural EF-hand sites, and serine, which is the most common (by far) non-acidic residue substitution at this position in EF-hand proteins in general, but never in parvalbumins. Results of the molecular dynamics simulations indicate that all three modifications are disruptive to the integrity of the mutated Ca 2+  binding site in the whole parvalbumin protein. In contrast, only the arginine and cysteine mutations are disruptive to the integrity of the mutated Ca 2+  binding site in the CD fragment of the parvalbumin protein. Surprisingly, the serine variant of the CD helix–loop–helix fragment exhibited remarkable stability during the entire molecular dynamics simulation, with retention of the Ca 2+  binding site. These results indicate that there are no inherent problems (for Ca 2+  ion binding) associated with the sequence of the CD helix–loop–helix fragment that precludes the incorporation of serine at the gateway position. Since the CD site is totally disrupted in the whole protein serine variant, this indicates that the Ca 2+  ion binding deficiencies are most likely related to the unique interaction that exists between the paired EF-hands in the whole protein. Our theoretical results correlate well with previous studies on engineered EF-hand proteins and with all of our experimental evidence on the silver hake parvalbumin.

Molecular dynamics study of Ca 2+ binding loop variants of parvalbumin with modifications at the `gateway' position