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Multiscale computer simulation of the immature HIV-1 virion.

ABSTRACT: Multiscale computer simulations, employing a combination of experimental data and coarse-graining methods, are used to explore the structure of the immature HIV-1 virion. A coarse-grained (CG) representation is developed for the virion membrane shell and Gag polypeptides using molecular level information. Building on the results from electron cryotomography experiments, the simulations under certain conditions reveal the existence of an incomplete p6 hexameric lattice formed from hexameric bundles of the Gag CA domains. In particular, the formation and stability of the immature Gag lattice at the CG level requires enhanced interfacial interactions of the CA protein C-terminal domains (CTDs). An exact mapping of the CG representation back to the molecular level then allows for detailed atomistic molecular dynamics studies to confirm the existence of these enhanced CA(CTD) interactions and to probe their possible origin. The multiscale simulations further provide insight into potential CA(CTD) mutations that may disrupt or modify the Gag immature lattice assembly process in the immature HIV-1 virion.

SUBMITTER: Ayton GS

PROVIDER: S-EPMC2966041 | biostudies-literature | 2010 Nov

REPOSITORIES: biostudies-literature

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Multiscale computer simulation of the immature HIV-1 virion.

Ayton Gary S GS Voth Gregory A GA

Biophysical journal 20101101 9

Multiscale computer simulations, employing a combination of experimental data and coarse-graining methods, are used to explore the structure of the immature HIV-1 virion. A coarse-grained (CG) representation is developed for the virion membrane shell and Gag polypeptides using molecular level information. Building on the results from electron cryotomography experiments, the simulations under certain conditions reveal the existence of an incomplete p6 hexameric lattice formed from hexameric bundl ...[more]

PMID: 21044572

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Project description:Syringomyelia is a pathological condition in which fluid-filled cavities (syringes) form and expand in the spinal cord. Syringomyelia is often linked with obstruction of the craniocervical junction and a Chiari malformation, which is similar in both humans and animals. Some brachycephalic toy breed dogs such as Cavalier King Charles Spaniels (CKCS) are particularly predisposed. The exact mechanism of the formation of syringomyelia is undetermined and consequently with the lack of clinical explanation, engineers and mathematicians have resorted to computer models to identify possible physical mechanisms that can lead to syringes. We developed a computer model of the spinal cavity of a CKCS suffering from a large syrinx. The model was excited at the cranial end to simulate the movement of the cerebrospinal fluid (CSF) and the spinal cord due to the shift of blood volume in the cranium related to the cardiac cycle. To simulate the normal condition, the movement was prescribed to the CSF. To simulate the pathological condition, the movement of CSF was blocked.For normal conditions the pressure in the SAS was approximately 400 Pa and the same applied to all stress components in the spinal cord. The stress was uniformly distributed along the length of the spinal cord. When the blockage between the cranial and spinal CSF spaces forced the cord to move with the cardiac cycle, shear and axial normal stresses in the cord increased significantly. The sites where the elevated stress was most pronounced coincided with the axial locations where the syringes typically form, but they were at the perimeter rather than in the central portion of the cord. This elevated stress originated from the bending of the cord at the locations where its curvature was high.The results suggest that it is possible that repetitive stressing of the spinal cord caused by its exaggerated movement could be a cause for the formation of initial syringes. Further consideration of factors such as cord tethering and the difference in mechanical properties of white and grey matter is needed to fully explore this possibility.

Dataset Information

Multiscale computer simulation of the immature HIV-1 virion.

Publications

Multiscale computer simulation of the immature HIV-1 virion.

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