Integrated Analysis of Residue Coevolution and Protein Structures Capture Key Protein Sectors in HIV-1 Proteins

<div><p>HIV type 1 (HIV-1) is characterized by its rapid genetic evolution, leading to challenges in anti-HIV therapy. However, the sequence variations in HIV-1 proteins are not randomly distributed due to a combination of functional constraints and genetic drift. In this study, we examined patterns of sequence variability for evidence of linked sequence changes (termed as coevolution or covariation) in 15 HIV-1 proteins. It shows that the percentage of charged residues in the coevolving residues is significantly higher than that in all the HIV-1 proteins. Most of the coevolving residues are spatially proximal in the protein structures and tend to form relatively compact and independent units in the tertiary structures, termed as “protein sectors”. These protein sectors are closely associated with anti-HIV drug resistance, T cell epitopes, and antibody binding sites. Finally, we explored candidate peptide inhibitors based on the protein sectors. Our results can establish an association between the coevolving residues and molecular functions of HIV-1 proteins, and then provide us with valuable knowledge of pathology of HIV-1 and therapeutics development.</p></div

HIV protein sectors underlying conserved, independently varying biological activities.

<p>(A) The coevolving residues in RT enzyme were located near the three catalytically essential amino acid residues (Asp110, Asp185, and Asp186) for polymerase catalysis. (B) For gp120, the coevolving residues were located near the protein-protein interface between gp120 and CD40, especially for Glu267, Glu268, Thr278 and Asp279. (C) For VPU protein, 6 out of 12 coevolving residues in the protein sector are charged amino acids. The figures were generated using PyMol (<a href="http://www.pymol.Org" target="_blank">http://www.pymol.Org</a>). The protein structures were colored with a default spectrum of rainbow colors in Pymol. The mesh surfaces of the coevolving residues were added while the different colors correspond to different amino acid residues.</p

The Importance of Bulk Viscoelastic Properties in “Self-Healing” of Acrylate-Based Copolymer Materials

“Self-healing” has emerged as a concept to increase the functional stability and durability of polymer materials in applications and thus to benefit the sustainability of polymer-based technologies. Recently, van der Waals (vdW)-driven “self-healing” of sequence-controlled acrylate-based copolymers due to “key-and-lock”- or “ring-and-lock”-type interactions has generated considerable interest as a viable route toward engineering polymers with “self-healing” ability. This contribution systematically evaluates the time, temperature, and composition dependence of the mechanical recovery of acrylate-based copolymer and homopolymer systems subject to cut-and-adhere testing. “Self-healing” in n-butyl acrylate/methyl methacrylate (BA/MMA)- or n-butyl acrylate/styrene (BA/Sty)-based copolymers with varying composition and sequence is found to correlate with the bulk viscoelastic properties of materials and to follow a similar trend as other tested acrylate-based homo- and copolymers. This suggests that “self-healing” in this class of materials is more related to the chain dynamics of bulk materials rather than composition- or sequence-dependent specific interactions

RMSF plot during molecular dynamic simulations.

<p>The figure shows backbone RMSF of GP120 (A), IN (B), and NEF (C) in molecular dynamics simulations of 10 ns. The x-axis represents protein sequences while the y-axis is average RMSF values.</p

Evidence for molecular functions of protein sectors in HIV-1 proteins.

<p>Evidence for molecular functions of protein sectors in HIV-1 proteins.</p

Epitopes of CD4+/CD8+ T lymphocytes for gp120 protein.

<p>The epitopes of CD4+ (A) and CD8+ (B) T lymphocytes in protein sector of gp120 protein.</p

Coevolution patterns in 15 HIV-1 proteins.

<p>The panels (A-L) are heat maps of the direct information (DI) values of residue pairs in multiple sequence alignments of GP120, GP41, MA, CA, NC, PR, RT, IN, P6, NEF, REV, TAT, VIF, VPR, and VPU, respectively. The x- and y-axes represent the positions of amino acid residues in the multiple sequence alignments with gap filtering (see <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0117506#sec010" target="_blank">Methods</a>).</p

Coevolution networks of HIV-1 proteins.

<p>The nodes represent the amino acid residues in HIV-1 proteins while the edges are the coevolving relationships among the residues. The amino acid labels come from the protein tertiary structures (<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0117506#pone.0117506.t002" target="_blank">Table 2</a>). The proteins are classified into three categories, including structural proteins (A), viral enzymes (B), and accessory proteins (C).</p

Interactions between coevolving residues in GP120.

<p>(A) The contact (hydrogen bonds) maps from molecular dynamics simulation of GP120; (B-F) Snapshots of the interactions between coevolving residues in protein sector of gp120 during molecular dynamics simulations of 0 ns, 1 ns, 2 ns, 5 ns, and 10 ns separately.</p

The top frequent residue pairs in HIV proteins.

<p>The top frequent residue pairs in HIV proteins.</p