Abstract
The WW domain consists of ∼40 residues, has no disulfide bridges, and forms a three-stranded antiparallel β-sheet that is monomeric in solution. It thus provides a model system for studying β-sheet stability in native proteins. We performed molecular dynamics simulations of two WW domains, YAP65 and FBP28, with very different stability characteristics, in order to explore the initial unfolding of the β-sheet. The less stable YAP domain is much more sensitive to simulation conditions than the FBP domain. Under standard simulation conditions in water (with or without charge-balancing counterions) at 300 K, the β-sheet of the YAP WW domain disintegrated at early stages of the simulations. Disintegration commenced with the breakage of a hydrogen bond between the second and third strands of the β-sheet due to an anticorrelated transition of the Tyr-28 ψ and Phe-29 ϕ angles. Electrostatic interactions play a role in this event, and the YAP WW domain structure is more stable when simulated with a complete explicit model of the surrounding ionic strength. Other factors affecting stability of the β-sheet are side-chain packing, the conformational entropy of the flexible chain termini, and the binding of cognate peptide.
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