Son Tung Ngo

Fast and accurate determination of the relative binding affinities of small compounds to HIV-1 protease using non-equilibrium work.

The fast pulling ligand (FPL) out of binding cavity using non‐equilibrium molecular dynamics (MD) simulations was demonstrated to be a rapid, accurate and low CPU demand method for the determination of the relative binding affinities of a large number of HIV‐1 protease (PR) inhibitors. In this approach, the ligand is pulled out of the binding cavity of the protein using external harmonic forces, and the work of pulling force corresponds to the relative binding affinity of HIV‐1 PR inhibitor. The correlation coefficient between the pulling work and the experimental binding free energy of R=−0.95 shows that FPL results are in good agreement with experiment. It is thus easier to rank the binding affinities of HIV‐1 PR inhibitors, that have similar binding affinities because the mean error bar of pulling work amounts to δW=7% . The nature of binding is discovered using the FPL approach.

Replica exchange molecular dynamics study of the amyloid beta (11–40) trimer penetrating a membrane

Alzheimers disease is characterized by the interaction of neurotoxic Aβ oligomers with cellular membranes, which disturbs ion homeostasis. To determine the putative structures of the transmembrane 3Aβ11–40 oligomer, temperature replica exchange molecular dynamics (REMD) simulations with an explicit solvent have been employed to monitor the structural changes when interaction of the oligomer with the membrane DPPC lipid bilayer is induced. Although the initial conformation of the 3Aβ11–40 transmembrane was fibril-like, the obtained results are in good agreement with previous experiments, in which the β-structure of the Aβ oligomer represents ∼40% of the structure in the average of all considered snapshots. The statistical coil structure, which is located near and interacts with the membrane headgroups, amounts to almost 60% of the structure. The transmembrane Aβ oligomer helix structure basically disappears during the REMD simulations. Instead of the Asp23–Lys28 salt bridge, the polar contact between Asp23 and Asn27 has been found to be a factor stabilizing the structure of the Aβ oligomer. Although numerous polar contacts between lipid headgroups and the peptide have been found, free energy perturbation calculations indicated that van der Waals interactions are the key factor determining the binding between the Aβ trimer and the membrane. It may be argued that the Aβ11–40 trimer can be easily inserted into the membrane because the binding free energy between the trimer and the membrane reaches −70 kcal mol−1. The collision cross section of the optimized structures of 1341 ± 23 A2 agrees well with the experimental values for the solvated Aβ trimer.

In silico studies of solvated F19W amyloid β (11–40) trimer

Alzheimers disease (AD) is associated with the oligomerization and/or fibrillation of amyloid beta (Aβ) peptides, which cause damage to brain cells. Aβ oligomers and fibrils contain hydrophobic cores formed with parallel beta sheets. Mutations of F19, a residue in the hydrophobic core of Aβ peptides, slow down their aggregation process but do not alter the overall structure of the resulting fibrils. However, the effects of F19 mutations on the toxic Aβ oligomers have not been elucidated. We studied the F19W mutant of the 11–40 truncated Aβ trimer (F19W 3Aβ11–40) using replica exchange molecular dynamics (REMD) simulations. While most structural terms do not change significantly, critical polar contacts decrease by 20%, and notably, RMSD almost doubles upon F19W mutation. Six minima were found in the free energy surface of F19W 3Aβ11–40, which have lower energy barriers (by ∼1 kJ mol−1) and significantly lower total population (∼20%) compared to those of the three minima found for 3Aβ11–40 (∼60%). The binding free energy between constituting chains of the mutant trimer increases by ∼28 kcal mol−1 but fluctuates significantly (±27.1 kcal mol−1). Our results indicate that while the hydrophobic core of amyloid beta peptide is capable of adapting to structural changes, F19W mutation results in a significantly more flexible trimer. The more flexible F19W mutant oligomers would require more time to self-assemble into fibrils. Our results contribute to a better understanding of the behavior of Aβ peptides and their oligomerization/aggregation process, which is necessary to understand AD pathogenesis.

Evaluation of the absolute affinity of neuraminidase inhibitor using steered molecular dynamics simulations

The absolute free energy difference of binding (ΔG) between neuraminidase and its inhibitor was evaluated using fast pulling of ligand (FPL) method over steered molecular dynamics (SMD) simulations. The metric was computed through linear interaction approximation. Binding nature was described by free energy differences of electrostatic and van der Waals (vdW) interactions. The finding indicates that vdW metric is dominant over electrostatics in binding process. The computed values are in good agreement with experimental data with a correlation coefficient of R=0.82 and error of σΔGexp=2.2kcal/mol. The results were observed using Amber99SB-ILDN force field in comparison with CHARMM27 and GROMOS96 43a1 force fields. Obtained results may stimulate the search for an Influenza therapy.

Theoretical study of the interactions between the first transmembrane segment of NS2 protein and a POPC lipid bilayer

Non-structural protein 2 (NS2) plays a crucial role in the hepatitis C virus (HCV) assembly. NS2 was predicted to be composed of three transmembrane (TM) segments. However, the mechanism of interactions between TM segments of NS2 and surrounding lipid environment remains unclear. Molecular dynamics simulations were applied to investigate the conformation and orientation of the first transmembrane segment (TM1) as well as the interactions of TM1 with a zwitterionic POPC lipid bilayer which identifies several key residues that stabilize the position of TM1 within the membrane. Along with the charged residues R3 and K27, the S23 and H25 were found to be the key elements in establishing the conformation of TM1 inside the membrane. The peptide forms a stable α-helix (the sequence 12-21) connected to N-terminal haft in POPC bilayer. The results also reveal that TM1 induces the ordering of lipid and does not destabilize the lipid bilayer system. The hydrophobic mismatch in which the segment tilts an angle along the membrane normal was observed in this system. The binding free energy profile of TM1 to the membrane was also estimated using umbrella sampling.