Zhi-Yuan Su

Homology modeling, docking, and molecular dynamics reveal HR1039 as a potent inhibitor of 2009 A(H1N1) influenza neuraminidase

The neuraminidase of the influenza virus is the target of antiviral drugs oseltamivir and zanamivir. Clinical practices have shown that zanamivir and oseltamivir are effective in treating the 2009 A(H1N1) influenza virus. However, drug resistance strains are also emerging. Herein, we report the findings from homology modeling and molecular simulations of 2009 A(H1N1) neuraminidase complexed with zanamivir, oseltamivir, and several herb extracts with potential activities. Our docked oseltamivir and zanamivir results are consistent with previous studies. Based on the same procedure, the docked results of herb extracts HR1039 and HR1040 suggest that they are potential potent inhibitors of neuraminidase. Also, the binding modes of HR1039/HR1040 are different from those of oseltmivir and zanamivir, and may be effective in treating oseltamivir-resistant influenza virus strains.

Coarse-grained molecular dynamics simulations of cobra cytotoxin A3 interactions with a lipid bilayer: penetration of loops into membranes.

Cobra cytotoxins, which are small three-looped proteins composed of approximately 60 amino acid residues, primarily act by destroying the bilayer membranes of cells and artificial vesicles. However, the molecular mechanism governing this process is not yet completely understood. We used coarse-grained molecular dynamics (CGMD) simulations to study the mechanism underlying the penetration of cardiotoxin A3 (CTX A3), the major toxic component of Naja atra (Chinese cobra) venom, into a hydrated 1-palmitoyl-2-oleoyl-1-sn-3-phosphatidylcholine (POPC) lipid bilayer. We performed CGMD simulations for three different conformations of the cobra cytotoxin-the tail, lying, and harrow conformations. The results of our simulations indicate that two of these, the tail and lying conformations, did not penetrate the bilayer system. Further, for the harrow conformation, loops 2 and 3 played important roles in penetration of CTX A3 into the bilayer system.

Potential of mean force for Syrian hamster prion epitope protein – Monoclonal fab 3f4 antibody interaction studies

Simulating antigen-antibody interactions are crucial for understanding antigen-antibody associations in immunology. To shed further light on this question, we study a dissociation of the Syrian hamster prion epitope protein-fab 3f4 antibody complex structure. The stretching, that is, the distance between the center of mass of the prion epitope protein and the fab 3f4 antibody, has been studied using potential of mean force (PMF) calculations based on molecular dynamics (MD) and the implicit water model. For the complex structure, there are four important intermediates, U-shaped groove on the antibodies, and two inter-protein molecular hydrogen bonds in the stretching process. Use of our simulations may help in understanding the binding mechanics of the complex structure, and thus of significance in the design of antibodies against prion disease.

Potential of mean force of the hepatitis C virus core protein-monoclonal 19D9D6 antibody interaction.

Antigen-antibody interactions are critical for understanding antigen-antibody associations in immunology. To shed further light on this question, we studied a dissociation of the 19D9D6-HCV core protein antibody complex structure. However, forced separations in single molecule experiments are difficult, and therefore molecular simulation techniques were applied in our study. The stretching, that is, the distance between the center of mass of the HCV core protein and the 19D9D6 antibody, has been studied using the potential of mean force calculations based on molecular dynamics and the explicit water model. Our simulations indicate that the 7 residues Gly70, Gly72, Gly134, Gly158, Glu219, Gln221 and Tyr314, the interaction region (antibody), and the 14 interprotein molecular hydrogen bonds might play important roles in the antigen-antibody interaction, and this finding may be useful for protein engineering of this antigen-antibody structure. In addition, the 3 residues Gly134, Gly158 and Tyr314 might be more important in the development of bioactive antibody analogs.

A Molecular Dynamics Simulation of the Human Lysozyme – Camelid VHH HL6 Antibody System

Amyloid diseases such as Alzheimer’s and thrombosis are characterized by an aberrant assembly of specific proteins or protein fragments into fibrils and plaques that are deposited in various tissues and organs. The single-domain fragment of a camelid antibody was reported to be able to combat against wild-type human lysozyme for inhibiting in-vitro aggregations of the amyloidogenic variant (D67H). The present study is aimed at elucidating the unbinding mechanics between the D67H lysozyme and VHH HL6 antibody fragment by using steered molecular dynamics (SMD) simulations on a nanosecond scale with different pulling velocities. The results of the simulation indicated that stretching forces of more than two nano Newton (nN) were required to dissociate the proteinantibody system, and the hydrogen bond dissociation pathways were computed.

Target molecular simulations of RecA family protein filaments.

Modeling of the RadA family mechanism is crucial to understanding the DNA SOS repair process. In a 2007 report, the archaeal RadA proteins function as rotary motors (linker region: I71-K88) such as shown in Figure 1. Molecular simulations approaches help to shed further light onto this phenomenon. We find 11 rotary residues (R72, T75-K81, M84, V86 and K87) and five zero rotary residues (I71, K74, E82, R83 and K88) in the simulations. Inclusion of our simulations may help to understand the RadA family mechanism.

Binding in Human Antibody-DNA Interface: A Computer-Simulation Study

The stretching, that is, the distance between the centre of mass of the ssDNA and the antibody, has been studied using the potential of mean force calculations based on molecular dynamics and the explicit water model. Our simulations indicate that the 6 residues Gln43, Gly44, Arg98, Tyr100, Val136 and Thr137, pair interactions of antibody-ssDNA, and the 5 interprotein molecular hydrogen bonds might play important roles in the antibody-ssDNA interaction, and this finding may be useful for protein engineering of this antibody-ssDNA structure. In addition, the 6 residues Gln43, Gly44, Arg98, Tyr100, Val136 and Thr137 might be more important in the development of bioactive antibody analogues.

Modelling and predicting the binding mechanics of HIV P1053-0.5β antibody complex

Simulating antigen–antibody interactions is crucial in understanding the mechanics of antigen–antibody binding in medical science. In this study, molecular dynamics simulations are performed to analyse the dissociation of the P1053-0.5β antibody complex structure. The two-dimensional free energy profiles of the complex structure are extracted using the weighted histogram analysis method, and the binding pathway is then predicted using a modified form of the MaxFlux-PRM method. The simulation results suggest that 10 amino residues (i.e. Leu11, Val13, Asp34, Arg112, Thr101, Gly127, Val229, Ser231, Ile235 and Arg236) play a key role in relaxing the antibody structure, thereby facilitating the binding of the 0.5β antibody-P1053 peptide system.