Pisum sativum defensin 2 (Psd2) is a small (4.7 kDa) antifungal peptide whose structure is held together by four conserved disulfide bridges. Psd2 shares the cysteine‐stabilized alpha‐beta (CSαβ) fold, which lacks a regular hydrophobic core. All hydrophobic residues are exposed to the surface, except for leucine 6. They are clustered in the surface formed by two loops, between β1 and α‐helix and β2 and β3 sheets. The observation of surface hydrophobic clusters reveals a remarkable evolution of the CSαβ fold to expose and reorganize hydrophobic residues, which facilitates creating versatile binding sites.

In this review, we briefly describe a theoretical discussion of protein folding, presenting the relative contribution of the hydrophobic effect versus the stabilization of proteins via direct surface forces that sometimes may be overlooked. We present NMR-based studies showing the stability of proteins lacking a hydrophobic core which in turn present hydrophobic surface clusters, such as plant defensins. Protein dynamics measurements by NMR are the key feature to understand these dynamic surface clusters. We contextualize the measurement of protein dynamics by nuclear relaxation and the information available at protein surfaces and water cavities. We also discuss the presence of hydrophobic surface clusters in multidomain proteins and their participation in transient interactions which may regulate the function of these proteins. In the end, we discuss how surface interaction regulates the reactivity of certain protein post-translational modifications, such as S-nitrosation.

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