Protein Surface Interactions-Theoretical and Experimental Studies

Abstract

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.

Keywords: NMR; clusters; dynamics; hydrophobic surface clusters; interdomain; solvation; surface.

FIGURE 1

Surface direct forces: amino acid residues exposed to the surface bridged by hydrogen bonds and VDW interaction with water (dash). (A) Lysine and aspartic acid as an example of two polar amino-acid side chains bridged by water molecules; (B) Leucine and alanine side-chains as an example of two apolar amino-acid side chains and the VDW interactions; (C) Leucine and aspartic acid as an example of apolar and polar amino-acid side chains.

FIGURE 2

Examples of hydrophobic residues exposing to solvent forming a hydrophobic/hydrophilic surface cluster in plant defensins. The extended and hydrophilic side chains of some amino acids are showing to protect the surface patch in (A,B) plant defensins Psd1; (C,D) Psd2; and (E,F) Sd5.

FIGURE 3

Representation of transient interdomain interactions and surface cluster patch. (A) Scheme of a hypothetic open/close equilibrium being regulated through inter-domain transient interaction. The two domains (blue circumference) linked by an intrinsically disordered region (IDR) are interacting in a close conformation through the transient binding of a “sticky” surface (pink), and the solvent-induced interaction in an open conformation. The transient binding sites (“sticky surfaces”) can be formed by defective packing, which may lead to insufficiently dehydrated hydrogen bonds and exposed hydrophobic residues. The blue dots denote the hydration shell formed by transient water molecules; (B) The Sis1 J-domain showing the surface patch with exposed hydrophobic residues (purple) protected by polar side chains (blue). This surface patch presents transient inter-domain interactions which are pivotal for protein recognition (Pinheiro et al., 2019).

FIGURE 4

Surface effect on the reactivity of S-nitrosation site. (A) Surface interactions modulating–SNO group in the protein; (B) RSNO as three resonance structures; (C) The protein environment driving nucleophilic attack in different positions in the RSNO.