Backbone Free Energy Estimator Applied to Viral Glycoproteins

Abstract

Earlier analysis of the Protein Data Bank derived the distribution of rotations from the plane of a protein hydrogen bond donor peptide group to the plane of its acceptor peptide group. The quasi Boltzmann formalism of Pohl-Finkelstein is employed to estimate free energies of protein elements with these hydrogen bonds, pinpointing residues with a high propensity for conformational change. This is applied to viral glycoproteins as well as capsids, where the 90th+ percentiles of free energies determine residues that correlate well with viral fusion peptides and other functional domains in known cases and thus provide a novel method for predicting these sites of importance as antiviral drug or vaccine targets in general. The method is implemented at https://bion-server.au.dk/hbonds/ from an uploaded Protein Data Bank file.

Keywords: antiviral drugs; vaccine targets; viral glycoproteins.

FIG. 1.

Two peptide groups, P_i, P_j, are depicted on the left, participating in a hydrogen bond with donor P_i and acceptor P_j. The planes of these peptide groups are illustrated in gray. There is a unique 3d rotation $A_{P_i}$ carrying the (oriented) xz plane to the gray plane for P_i and sending the positive x-axis to the ray $\overrightarrow{C_i{N}_{i+1}}$, and likewise $A_{P_j}$ for P_j. The composition $A_{P_i}^{-1}{A}_{P_j}$ illustrated on the right is the rotation in SO(3) associated to the pair P_i, P_j. See Section 5.2. for details.

FIG. 2.

As explained in Section 5.2., SO(3) may be visualized as a 3D ball of radius π. Presented here are 81 horizontal slices of the histogram of backbone hydrogen bond (BHBs) in HQ60 in this ball from north to south pole colored by population density from Penner et al. (2014), where the R-Y-G-B color is linear in the density ranging from 19,000 to 1.

FIG. 3.

Histogram of Π-values and of flanking Dictionary of Secondary Structure for Proteins (DSSP) secondary structure types across HQ60. (a) Histogram of Π(p) = ln(d(m)/d(p)) for all BHBs across HQ60. The x-axis corresponds to the indicated intervals of II-values achieved for the BHBs in HQ60, and the y-axis indicates the number of occurrences in HQ60 within each interval of size 0.18. (b) Population of flanking DSSP secondary structure types H (α helix), E (β strand), C (coil), B (β bridge), G (3₁₀ helix), 1 (π helix), S (bend), and T (turn) across the range of Π-values divided by 10 along the x-axis.

FIG. 4.

Compare with Figure 6 in White et al. (2008), to which these images are aligned. Blue indicates non-exotic, and yellow, orange, and red, respectively, correspond to Π-values at least 7.5, 8.5, and 9.5. Influenza hemagglutinin (HA; a,b) prefusion and (c,d) postfusion. Paramyxovirus glycoprotein F (e,f) prefusion and (g,h) postfusion. Tick-borne encephalitis glycoprotein E (i) prefusion and (j,k) postfusion. Vesicular stomatitis glycoprotein G (l,m) prefusion and (n,o) postfusion.

FIG. 6.

Paramyxovirus F prefusion, chain A on the left and chain B on the right. There is only approximate consensus on significant free energies between chains A and B and chain C in Figure 4f.

FIG. 5.

Influenza type 2 HA pre- and postfusion, both HA1 and HA2. Chains E and F are depicted on the left, and full glycoprotein on the right.

FIG. 7.

Histogram of Π-values and flanking primary structure for all exotic BHBs across HQ60. Curves are colored by residue as indicated. Note the increasing frequency of glycine reflecting the presumably progressively contorted exotic features that the primary structure must support.