We will study the relationship between protein states involved in folding/collapse and with those involved in recognition especially concerning with DNA. The mechanisms governing molecular recognition by proteins and the transition of proteins from their unfolded state to their native state are fundamental biophysical questions that remain unanswered. We will relate the chemical potentials of peptide subdomains in various contexts to changes in solubility and conformation and thus ultimately to recognition and binding. Several proposed systems will be computationally tested in various multicomponent aqueous solutions. Our recent theoretical work suggests the solvent effect on the initial collapse toward folding and the early processes of molecular recognition have many common features. We will study the relation of solubility as a function of length and composition with respect to the available conformational manifold. We will use glycine oligomers as our model for the protein subdomain of UBX and the hinge-helix sequence of LacI. High precision free energy simulations and advances in approximate theory make the calculations of 2, 3 and even 4 component solutions feasible for these studies. We will calculate the chemical potential of these and other peptides and small proteins as well as the other solution components as a function of conformation and solution composition. Misfolded and unstructured domains represent important examples of disease states where the understanding of the recognition, self-recognition or folding process has important potential therapeutic implications. This is not a sequence to structure proposal. Rather we study the fundamental free energy surface of features common to all proteins and the relation to binding.
The mechanisms governing protein-DNA recognition and the transition of proteins from their unfolded state to their native state are unanswered fundamental biophysical questions. Refolding often occurs in DNA binding. Misfolded and unstructured domains represent important examples of disease states where the understanding of the recognition, or folding process has important potential therapeutic implications.
|Lynch, Gillian C; Perkyns, John S; Nguyen, Bao Linh et al. (2015) Solvation and cavity occupation in biomolecules. Biochim Biophys Acta 1850:923-31|
|Harris, Robert C; Pettitt, B Montgomery (2014) Effects of geometry and chemistry on hydrophobic solvation. Proc Natl Acad Sci U S A 111:14681-6|
|Truchon, Jean-François; Pettitt, B Montgomery; Labute, Paul (2014) A Cavity Corrected 3D-RISM Functional for Accurate Solvation Free Energies. J Chem Theory Comput 10:934-941|
|Karandur, Deepti; Wong, Ka-Yiu; Pettitt, B Montgomery (2014) Solubility and aggregation of Gly(5) in water. J Phys Chem B 118:9565-72|
|Tomar, Dheeraj S; Weber, Valéry; Pettitt, B Montgomery et al. (2014) Conditional solvation thermodynamics of isoleucine in model peptides and the limitations of the group-transfer model. J Phys Chem B 118:4080-7|
|Montgomery Pettitt, B (2013) The unsolved "solved-problem" of protein folding. J Biomol Struct Dyn 31:1024-7|
|Lin, Bin; Pettitt, B Montgomery (2011) Note: On the universality of proximal radial distribution functions of proteins. J Chem Phys 134:106101|
|Lin, Bin; Wong, Ka-Yiu; Hu, Char et al. (2011) Fast Calculations of Electrostatic Solvation Free Energy from Reconstructed Solvent Density using proximal Radial Distribution Functions. J Phys Chem Lett 2:1626-1632|
|Lin, Bin; Pettitt, B Montgomery (2011) Electrostatic solvation free energy of amino acid side chain analogs: implications for the validity of electrostatic linear response in water. J Comput Chem 32:878-85|
|Perkyns, John S; Lynch, Gillian C; Howard, Jesse J et al. (2010) Protein solvation from theory and simulation: Exact treatment of Coulomb interactions in three-dimensional theories. J Chem Phys 132:064106|
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