The secondary structure propensities of the residues in the studied peptides.

<p>The results were obtained using the time intervals of 40–200 ns.</p

The calculated secondary structure probabilities for the WT PrP106-126 and its two mutants A117V, H111S.

<p>The calculated secondary structure probabilities for the WT PrP106-126 and its two mutants A117V, H111S.</p

Distributions of hydrophobic solvent accessible areas of WT PrP106-126 and its two mutants A117V, H111S.

<p>Hydrophobic SASA of residues Val, Met and Leu were considered.</p

Free energy surface (in Kcal/mol) for WT PrP106-126 and its two mutants A117V, H111S.

<p>Free energy surface (in Kcal/mol) for WT PrP106-126 and its two mutants A117V, H111S.</p

Representative β-hairpins and β-sheets from REMD of monomeric PrP106–126.

<p>Representative β-hairpins and β-sheets from REMD of monomeric PrP106–126.</p

The side chain-side chain contact maps of WT, A117V and H111S in 40-200ns time intervals.

<p>The right column represents substracted contact maps between A117V and WT and between H111S and WT. The (i,i), (i,i±1) and (i,i±2) contacts are not included.</p

Exploring the Molecular Mechanism of Cross-Resistance to HIV‑1 Integrase Strand Transfer Inhibitors by Molecular Dynamics Simulation and Residue Interaction Network Analysis

The rapid emergence of cross-resistance to the integrase strand transfer inhibitors (INSTIs) has become a serious problem in the therapy of human immunodeficiency virus type 1 (HIV-1) infection. Understanding the detailed molecular mechanism of INSTIs cross-resistance is therefore critical for the development of new effective therapy against cross-resistance. On the basis of the homology modeling constructed structure of tetrameric HIV-1 intasome, the detailed molecular mechanism of the cross-resistance mutation E138K/Q148K to three important INSTIs (Raltegravir (RAL, FDA approved in 2007), Elvitegravir (EVG, FDA approved in 2012), and Dolutegravir (DTG, phase III clinical trials)) was investigated by using molecular dynamics (MD) simulation and residue interaction network (RIN) analysis. The results from conformation analysis and binding free energy calculation can provide some useful information about the detailed binding mode and cross-resistance mechanism for the three INSTIs to HIV-1 intasome. Binding free energy decomposition analysis revealed that Pro145 residue in the 140s 1oop (Gly140 to Gly149) of the HIV-1 intasome had strong hydrophobic interactions with INSTIs and played an important role in the binding of INSTIs to HIV-1 intasome active site. A systematic comparison and analysis of the RIN proves that the communications between the residues in the resistance mutant is increased when compared with that of the wild-type HIV-1 intasome. Further analysis indicates that residue Pro145 may play an important role and is relevant to the structure rearrangement in HIV-1 intasome active site. In addition, the chelating ability of the oxygen atoms in INSTIs (e.g., RAL and EVG) to Mg²⁺ in the active site of the mutated intasome was reduced due to this conformational change and is also responsible for the cross-resistance mechanism. Notably, the cross-resistance mechanism we proposed could give some important information for the future rational design of novel INSTIs overcoming cross-resistance. Furthermore, the combination use of molecular dynamics simulation and residue interaction network analysis can be generally applicable to investigate drug resistance mechanism for other biomolecular systems

Ensemble-averaged secondary structure fraction for each residue of PrP106–126.

<p>Seven secondary structure elements are turn, β-bridge, α-helix, 3–10 helix, π-helix, coil and β-sheet, respectively.</p

The evolution of secondary structure.

<p>(a) Three peptides in trimer forming simulation. From the top to bottom, Chain A, Chain B and Chain C were displayed in order. (b) four peptides in tetramer forming simulation. Chain A, Chain B, Chain C and Chain D are illustrated in order from top to bottom.</p

Last snapshots of the simulations and the detailed illustrations of β-hairpin acquired by the two stable trimers.

<p>The ending structures were colored based on secondary structure. The residues forming the β-hairpin were shown in Licorice and colored according to names of atoms.</p