Sub-Nanoscale Surface Ruggedness Provides a Water-Tight Seal for Exposed Regions in Soluble Protein Structure

Abstract

Soluble proteins must maintain backbone hydrogen bonds (BHBs) water-tight to ensure structural integrity. This protection is often achieved by burying the BHBs or wrapping them through intermolecular associations. On the other hand, water has low coordination resilience, with loss of hydrogen-bonding partnerships carrying significant thermodynamic cost. Thus, a core problem in structural biology is whether natural design actually exploits the water coordination stiffness to seal the backbone in regions that are exposed to the solvent. This work explores the molecular design features that make this type of seal operative, focusing on the side-chain arrangements that shield the protein backbone. We show that an efficient sealing is achieved by adapting the sub-nanoscale surface topography to the stringency of water coordination: an exposed BHB may be kept dry if the local concave curvature is small enough to impede formation of the coordination shell of a penetrating water molecule. Examination of an exhaustive database of uncomplexed proteins reveals that exposed BHBs invariably occur within such sub-nanoscale cavities in native folds, while this level of local ruggedness is absent in other regions. By contrast, BHB exposure in misfolded proteins occurs with larger local curvature promoting backbone hydration and consequently, structure disruption. These findings unravel physical constraints fitting a spatially dependent least-action for water coordination, introduce a molecular design concept, and herald the advent of water-tight peptide-based materials with sufficient backbone exposure to remain flexible.

It Is Important to Compute Intramolecular Hydrogen Bonding in Drug Design?

“…To prevail in water environments, soluble proteins must protect their backbone hydrogen bonds from the disruptive effect of water attack by clustering nonpolar residues around them [252][253][254][255][256][257][258][259][260]. This exclusion of surrounding water, or wrapping effect, also enhances the electrostatic contribution by modulating the local dielectric (descreening the partial charges) and thus stabilizes the HB.…”

Communication: Epistructural thermodynamics of soluble proteins

“…6 Compared with bulk water (g = 4), interfacial water has reduced hydrogen-bonding opportunities (g < 4) and may counterbalance such losses by interacting with polar groups on the protein surface or with induced electrostatic fields resulting from preferred dipole alignments under confinement. 3,4 In regards to g(r) as computed in this work, only the first layer of the interface differs from bulk water, while water in outer layers invariably recapitulates bulk configurations. Thus, the usefulness of g(r) as descriptor of water structure requires a local one-layer resolution.…”

“…Epistructural attributes of soluble proteins refer to interfacial properties arising from the physical interaction between structure and solvent and have received comparatively little attention, partly because nanoscale models of interfacial water are still in development. [1][2][3][4][5][6] The most significant epistructural parameter is the solvent-structure interfacial tension (SSIT), that is, the reversible work per unit area required to span the solvent envelope of the protein structure. This epistructural tension has been estimated only recently, 6 despite its importance in determining protein associations, the basic molecular events in biological processes.…”

“…This epistructural tension has been estimated only recently, 6 despite its importance in determining protein associations, the basic molecular events in biological processes. A direct computation of the SSIT is difficult due to the confinement of the interfacial water within chemically and geometrically inhomogeneous nanoscale cavities 3,6 and the complications arising from the assignment of entropic costs to such confinements. To reduce the free-energy cost of spanning the interface, the SSIT promotes a highly controlled association of soluble proteins into specific complexes, while precluding proteins from amorphously precipitating to yield phase separations.…”

“…4 In accord with a nanoscale description of the solvent envelope, a rigorous SSIT derivation involves an elastic term that penalizes local losses in hydrogen-bonding coordination of interfacial water. Furthermore, the treatment allows for compensations to this entropic cost as water dipoles interact with pre-existing or confinement-induced electrostatic fields, 3,4 yielding a polarization whose magnitude depends on the local coordination restrictions of the water dipoles.…”