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Richard S. L. Stein CS 379a January 31, 2006

Dissociation of an antiviral compound from the internal pocket of human rhinovirus 14 capsid (Y. Li, Z. Zhou, and C. B. Post). Richard S. L. Stein CS 379a January 31, 2006. HRV and WIN 52084.

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Richard S. L. Stein CS 379a January 31, 2006

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  1. Dissociation of an antiviral compound from the internal pocket of human rhinovirus 14 capsid(Y. Li, Z. Zhou, and C. B. Post) Richard S. L. Stein CS 379a January 31, 2006

  2. HRV and WIN 52084 • HRV is in a class of human “rhino-viruses” (causes common cold, foot-and-mouth disease, hepatitis, etc.) • HRV is composed of four types of viral protein (VP1, VP2, VP3, VP4) • WIN 52084 is a hydrophobic compound that binds to a pocket within VP1 and inhibits the HRV uncoating (RNA-injection) mechanism

  3. HRV and WIN 52084 • A: WIN 52084 (purple) bound to VP1 (blue) in HRV • B: WIN 52084 structure • C: VP1 (blue)/VP3 (red) with WIN 52084 (not shown)

  4. Molecular Dynamics (MD) Simulations • Model the dissociation of WIN 52084 from the VP1 pocket to comprehend the mechanism of the ligand’s travel through the VP1 pathway • Capture equilibrium trajectories as a “control” for comparison • Turn on an external potential that “drives” the ligand away from the capsid, to expedite the dissociation process

  5. External Potential Strength a corresponds to biasing potential strength; ideal values are 0.0001 and 0.0005

  6. Results • D(DR) measures the dif-ference in the behavior of HRV protein residues, between WIN 52084 in equilibrium and WIN 52084 in dissociation • Greatest perturbations occur in specific residues of VP1; N- and C-termini of VP3; and N-terminus of VP4 • Residues 99—106 (VP1) form bC strand within pocket • I266 (VP1) is part of the pore; T88, P158, V163 line pathway near surface; E236 (VP3) covers pore opening

  7. Results • Large perturbations also observed for N-termini of VP3 and VP4 (which are never in contact with WIN 52084 during dissociation) • N-termini of VP3 & VP4 wrap the 5-fold axis of HRV to form annulus in the interior of the capsid (thought to be the opening through which RNA-injection occurs) • Large nanoscale fluctuations at N-termini of VP3 & VP4 are substantially reduced in presence of antiviral compound

  8. HRV (5-fold axis view) • Left: WIN 52084 (green) within VP1 pocket (blue); C-terminus of VP3 (red) at opening; N-termini of VP3 & VP4 (yellow) shown behind pocket • Right: Axial view of N-terminal residues of VP3 & VP4 (WIN 52084 does not directly interact with this area)

  9. Dissociation Mechanics • Transitions most clearly shown with a = 0.0001 kcal/mol·Å4 • WIN 52084 begins in bound conformation at dissociation coordinate 135 Å • Dissociation proceeds slowly in regions S2 and S3, and rapidly outside these regions • Complete solvation occurs at dissociation coordinate 170 Å (time 5 ns) • Simulation data suggests presence of energy barriers in regions S2 and S3

  10. Dissociation Pathway • A: WIN 52084 (yellow) dissociating from VP1 (blue) & VP3 (red) in HRV • B: Individual frames of WIN 52084 dissociation (0.0, 2.0, 3.5, 3.8, 4.1, 4.3 ns); only critical residues of VP1, VP3 shown

  11. Pathway Discussion • WIN 52084 must twist and bend in order to travel through the pocket of HRV • HRV residues in VP1 alter their conformations during trajectory • E236 (VP3) forms a cap which must move away from pocket opening • No structural features of HRV or interactions with WIN 52084 were found which corresponded to energy barriers in regions S2 and S3 • K103 (VP1) & E236 (VP3) form ion-pair at opening, but this interaction can be broken independent of antiviral compound

  12. How Much is Conformational Flexibility Needed? • WIN 52084 contains a fully saturated 7-carbon alkyl chain • All of the torsion angles rotate and undergo several transitions each during the dissociation simulations • Conclusion: flexibility is a desirable characteristic in an antiviral agent

  13. Drug Design Considerations • Many dihedral rotations for each C—C torsion angle are required for WIN 52084 to bind to HRV • Antiviral agents with one double bond, WIN 55865 and WIN 56278 (with a cis and a trans double bond respectively) have been studied on viruses in experiment • WIN 56278 (trans) binds 10 times more effectively than WIN 55865 (cis) suggesting that the trans compound adapts better to navigate the pore and hydrophobic pocket of the virus • In general, more flexible (more saturated) antiviral agents are better

  14. Possible Mechanisms for WIN Antiviral Activity • In HRV, the N-termini of VP1 and VP4 are drawn from the capsid interior to the surface, via the 5-fold axis, during the RNA-injection process • One explanation for WIN antiviral activity is entropic stabilization of the viral conformation at the 5-fold axis • WIN might also interfere with viral con-formational changes needed for RNA-injection • Conformational fluctuations in HRV, particularly in the N-termini of VP3 and VP4 (near the 5-fold axis), are greatly depressed in the presence of WIN (exact mechanism not known)

  15. Sample Discussion Questions • (i) What are some possible structural explana-tions for the energy barriers associated with the relatively long times spent by WIN 52084 in the S2 and S3 regions during dissociation? • (ii) How would one design a model for simulation, to study the physical basis for long-range effects of antiviral compounds?

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