This application proposes computational investigations of the properties of picornaviruses associated with antiviral activity and receptor recognition, and of the compressibility and structural: stability of globular proteins. Members of the virus family of Picornaviridae are causative agents of a broad spectrum of human and animal diseases initiated by attachment to cell surface receptors. Considerable effort has focused on the development of antiviral compounds against picornaviruses. The mechanism of antiviral activity, and the physical/chemical basis of receptor recognition will be examined by molecular dynamics simulation studies. Specific issues to be addressed include the long-range dynamic effects of antiviral compounds binding in an internal hydrophobic pocket of human rhinovirus (HRV) on the conformational properties of the virus. Based on previous results, it is proposed that long-range effects of antiviral compounds alter the dynamics of residues at the 5-fold symmetry axis, and that this response contributes to the antiviral activity of WIN compounds. We will explore this question using large-scale simulations. In addition, free-energy methods will be used to probe the basis of intercellular adhesion molecule 1 (ICAM-1) specificity for HRV and coxsackievirus (CV). Recent progress in the determination of structures of the picornavirus-receptor complexes from cryo-electron microscopy reconstruction provide a new opportunity for computational analysis to elucidate receptor recognition. Effects of receptor amino acid mutations on virus capsid binding, which cannot be explained from the structures, will be examined using free energy simulations. Finally, mechanisms of antiviral activity and receptor recognition are associated with fundamental physical properties of proteins, and computational studies based on questions related to stability, compressibility and solvation are also proposed. The detailed information of MD simulations will be exploited to elucidate a newly recognized correspondence between protein compressibility and energetics by defining the basis for stabilization of buried charge in proteins. The compressibility of hydration waters and analysis of protein solution compressibilities will also be probed. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
2R01AI039639-10A1
Application #
7195189
Study Section
Macromolecular Structure and Function B Study Section (MSFB)
Program Officer
Salomon, Rachelle
Project Start
1997-02-01
Project End
2012-01-31
Budget Start
2007-02-01
Budget End
2008-01-31
Support Year
10
Fiscal Year
2007
Total Cost
$253,750
Indirect Cost
Name
Purdue University
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
072051394
City
West Lafayette
State
IN
Country
United States
Zip Code
47907
Kuhn, Richard J; Dowd, Kimberly A; Beth Post, Carol et al. (2015) Shake, rattle, and roll: Impact of the dynamics of flavivirus particles on their interactions with the host. Virology 479-480:508-17
Dadarlat, Voichita M; Gorenstein, Lev A; Post, Carol Beth (2012) Prediction of protein relative enthalpic stability from molecular dynamics simulations of the folded and unfolded states. Biophys J 103:1762-73
Roy, Amitava; Post, Carol Beth (2012) Long-distance correlations of rhinovirus capsid dynamics contribute to uncoating and antiviral activity. Proc Natl Acad Sci U S A 109:5271-6
Roy, Amitava; Post, Carol Beth (2012) Detection of long-range concerted motions in protein by a distance covariance. J Chem Theory Comput 8:3009-3014
Roy, Amitava; Post, Carol Beth (2011) Microscopic Symmetry Imposed by Rotational Symmetry Boundary Conditions in Molecular Dynamics Simulation. J Chem Theory Comput 7:3346-3353
Ward, Joshua M; Gorenstein, Nina M; Tian, Jianhua et al. (2010) Constraining binding hot spots: NMR and molecular dynamics simulations provide a structural explanation for enthalpy-entropy compensation in SH2-ligand binding. J Am Chem Soc 132:11058-70
Dadarlat, Voichita M; Post, Carol Beth (2008) Contribution of charged groups to the enthalpic stabilization of the folded states of globular proteins. J Phys Chem B 112:6159-67
Dadarlat, Voichita M; Post, Carol Beth (2006) Decomposition of protein experimental compressibility into intrinsic and hydration shell contributions. Biophys J 91:4544-54
Li, Yumin; Zhou, Zhigang; Post, Carol Beth (2005) Dissociation of an antiviral compound from the internal pocket of human rhinovirus 14 capsid. Proc Natl Acad Sci U S A 102:7529-34
Dadarlat, Voichita M; Post, Carol Beth (2003) Adhesive-cohesive model for protein compressibility: an alternative perspective on stability. Proc Natl Acad Sci U S A 100:14778-83

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