Stickiness of the Hydrogen Bond

Abstract

The dielectric response of bulk water follows laws of continuum electrostatics, a scheme often extrapolated without justification to treat confined interfacial water, where the Debye polarization ansatz breaks down and discrete effects matter. Reconciling the discrete behavior with the continuum equations requires a conceptual leap, all the more so when assessing the electrostatic impact of exclusion of individual water molecules. This work takes up the challenge and identifies the nanoscale stickiness of a preformed water-embedded hydrogen bond as phenomena not encompassed by continuum laws but quantitatively predictable when adopting a nanoscale theory of dielectric response holding down to molecular dimensions. Nanoscale stickiness is known to drive basic cellular events and has been measured using a molecular force probe but its physical underpinnings and computation have been lacking so far. The findings reported may impact molecular design in bio-nanotechnology and shed light on standing challenges in biophysics, especially on the protein folding problem, where organized compaction of the protein chain following nucleating intramolecular hydrogen bonding demands explanation.

Structural Impact of Mutation D614G in SARS-CoV-2 Spike Protein: Enhanced Infectivity and Therapeutic Opportunity

“…Dehydrons were identified from PDB-reported structural coordinates of proteins − using a plugin to the PyMol platform (). To that end, we define the extent of hydrogen-bond wrapping, w , giving the number of side chain nonpolar groups (CH n , n = 1, 2, 3) contained within a ‘“desolvation domain”’ around the BHB.…”

“…In other words, the D614G mutation promotes the S1/S2 association because (a) it destabilizes the free (uncomplexed) S1 structure through the enhanced exposure of the BHB pairing residues G614 and A647 and (b) it stabilizes the S1/S2 interface as the D614G substitution decreases the intramolecular wrapping of the G614-A647 dehydron, thereby further promoting its intermolecular wrapping via the contribution from S2 residue P862 ( Figure 1 d). A conservative estimate drawn from experimental data on the cost of unwrapping the BHB (ref ( 8 ) Figure 3) gives 3 × 8 kJ/mol = 5.73 kcal/mol as the thermodynamic cost of destabilizing the S1 structure resulting from depriving the BHB 614–647 of three wrapping carbonaceous groups due to the D614G substitution. The lost wrapping contributions include one methylene group from the D → G substitution proper and two methylene groups from R646 that no longer can form the salt bridge with the glycine at position 614 (cf.…”

“…The preformed D614-A647 backbone hydrogen bond (BHB) is partially exposed to the solvent (Figure b), and hence it constitutes a special kind of packing defect known as dehydron − in the S1 domain. From a thermodynamic standpoint, the dehydron is an adhesive spot promoting removal of surrounding water , for two mutually reinforcing reasons: − (a) the preformed BHB gets stabilized when a protein association (i.e., S1/S2 interaction) causes removal of surrounding water thereby hindering the structurally disruptive hydration of amide and carbonyl (destabilizing the unbound state is tantamount to stabilize the bound state), and (b) the removal of backbone-solvating water molecules at the dehydron site is favorable because the partial confinement of such water molecules curtails their hydrogen bonding coordination possibilities; therefore, their transference to the bulk becomes thermodynamically supported . The dehydron adhesiveness can also be justified from an energetic standpoint, as the screening of partial charges paired by the BHB is removed concurrently with the removal of surrounding water molecules, thus strengthening the BHB …”

Artificial Intelligence Steering Molecular Therapy in the Absence of Information on Target Structure and Regulation

“…These regions generate interfacial tension and functionalize nearby phosphorylation-susceptible side chains; thus, they become essential to create peptide-based PPI disruptors within a rational discovery effort. The discovery is made possible because epistructural information or the structure-solvent dynamic relationship, is encoded in structural information 18,20,21 which the network is able to infer from 1D sequence-based input. At a preliminary level, the DL discovery platform is benchmarked by establishing the accuracy of epistructural inference on a PDB-derived testing set (Methods and Supporting Information).…”

“…21 Dehydrons are precisely the type of epistructural features endowed with the sought after dual role. 18,20 To summarize, the overarching aim of this work is the development of DL method to expand the pharmaceutical discovery platform to cases where there is no detailed information on target structure and regulation of target activity. We focus on the most challenging cases involving rational design of molecular disruptors of deregulated protein complexes whose recruitment leads to disease.…”