%0 Journal Article %1 hlwoodcock:T.1998-a %A van Vlijmen, H. W. T. %A Curry, S. %A Schaefer, M. %A Karplus, M. %D 1998 %J J. Mol. Biol. %K stability titration electrostatics simulation ph-stability structure virus replication lysozyme prediction computer protein poliovirus model bibtex-import curve histidine-residues program rhinovirus %N 2 %P 295--308 %T Titration calculations of foot-and-mouth disease virus capsids and their stabilities as a function of ph %V 275 %X Foot-and-mouth disease virus (FMDV), a non-enveloped picornavirus, is sensitive to acidic conditions. At pH values below 7 the icosahedral virus capsid, formed from 60 copies of a protomer containing four polypeptides (VP1 to 4), dissociates into 12 pentamers, releasing the viral RNA. Evidence suggests that this acid lability may assist FMDV cell entry via an endosomal pathway. Calculations of titration curves and pH- stabilitiy profiles are presented for three different strains of FMDV, O1BFS, A10(61) and A22 Iraq, and compared with experimental data for complete virions and empty capsids (which lack RNA). The finite difference Poisson-Boltzmann method was used for the calculation of electrostatic free energies with the solvent treated as a dielectric continuum. The inter- pentamer interface in the virus is formed by two protomers related by 2-fold icosahedral symmetry. As a simple model for inter-pentamer interactions, a dimer and two separate protomers were compared. The association free energy was computed by integrating the difference between the titration curves of the two species. The calculations reproduced the observed decrease in capsid stability at acidic pH but not the difference in pH sensitivities of the two type A viruses. It is shown that only residues within 15 Angstrom of the interface play a significant role in determining acid lability. For the experimentally studied pH range (5 to 7.6), histidine residues were found to dominate the PH-dependence of the stability. Two histidine residues in VP3, H142 and H145, are shown to have the greatest effect by virtue of their interactions with many polar residues across the inter-pentamer interface; the interaction of H142 with an alpha-helix in the opposite pentamer contributes only a small proportion of the destabilization energy. (C) 1998 Academic Press Limited.

@article{hlwoodcock:T.1998-a, abstract = {Foot-and-mouth disease virus (FMDV), a non-enveloped picornavirus, is sensitive to acidic conditions. At pH values below 7 the icosahedral virus capsid, formed from 60 copies of a protomer containing four polypeptides (VP1 to 4), dissociates into 12 pentamers, releasing the viral RNA. Evidence suggests that this acid lability may assist FMDV cell entry via an endosomal pathway. Calculations of titration curves and pH- stabilitiy profiles are presented for three different strains of FMDV, O1BFS, A10(61) and A22 Iraq, and compared with experimental data for complete virions and empty capsids (which lack RNA). The finite difference Poisson-Boltzmann method was used for the calculation of electrostatic free energies with the solvent treated as a dielectric continuum. The inter- pentamer interface in the virus is formed by two protomers related by 2-fold icosahedral symmetry. As a simple model for inter-pentamer interactions, a dimer and two separate protomers were compared. The association free energy was computed by integrating the difference between the titration curves of the two species. The calculations reproduced the observed decrease in capsid stability at acidic pH but not the difference in pH sensitivities of the two type A viruses. It is shown that only residues within 15 Angstrom of the interface play a significant role in determining acid lability. For the experimentally studied pH range (5 to 7.6), histidine residues were found to dominate the PH-dependence of the stability. Two histidine residues in VP3, H142 and H145, are shown to have the greatest effect by virtue of their interactions with many polar residues across the inter-pentamer interface; the interaction of H142 with an alpha-helix in the opposite pentamer contributes only a small proportion of the destabilization energy. (C) 1998 Academic Press Limited.}, added-at = {2006-06-16T05:03:46.000+0200}, author = {van Vlijmen, H. W. T. and Curry, S. and Schaefer, M. and Karplus, M.}, biburl = {https://www.bibsonomy.org/bibtex/2a2003d0a5687ca892e11c6b5c6c3b303/hlwoodcock}, citeulike-article-id = {569449}, comment = {YT717 J MOL BIOL}, interhash = {e8c99f8d68f28285d9289f2a529cbc5e}, intrahash = {a2003d0a5687ca892e11c6b5c6c3b303}, journal = {J. Mol. Biol.}, keywords = {stability titration electrostatics simulation ph-stability structure virus replication lysozyme prediction computer protein poliovirus model bibtex-import curve histidine-residues program rhinovirus}, number = 2, pages = {295--308}, priority = {2}, timestamp = {2006-06-16T05:03:46.000+0200}, title = {Titration calculations of foot-and-mouth disease virus capsids and their stabilities as a function of ph}, volume = 275, year = 1998 }