D. Thirumalai

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Motivated by recent mean-field theories of the structural glass transition and of the Potts glass model we formulate a scaling and droplet picture of an assumed ideal structural glass transition. The phase transition is a random first-order phase transition where the supercooled-liquid phase is composed of glassy clusters separated by interfaces or domain walls. Because of entropic driving forces the glassy clusters are continually being created and destroyed. As the ideal transition temperature is approached the entropic driving force vanishes and the size of the glassy clusters diverges with an exponent of \ensuremath{\nu}=2/d. All long-time dynamical processes are activated and the Vogel-Fulcher law is obtained for the liquid-state relaxation time.

The presence of macromolecules in cells geometrically restricts the available space for poplypeptide chains. To study the effects of macromolecular crowding on folding thermodynamics and kinetics, we used an off-lattice model of the all-β-sheet WW domain in the presence of large spherical particles whose interaction with the polypeptide chain is purely repulsive. At all volume fractions, ϕ c , of the crowding agents the stability of the native state is enhanced. Remarkably, the refolding rates, which are larger than the value at ϕ c = 0, increase nonmonotonically as ϕ c increases, reaching a maximum at \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \setlength{\oddsidemargin}{-69pt} \begin{document} \begin{equation*}{\varphi}_{{\mathrm{c}}}={\varphi}_{{\mathrm{c}}}^{*}\end{equation*}\end{document} . At high values of ϕ c , the depletion-induced intramolecular attraction produces compact structures with considerable structure in the denatured state. Changes in native state stability and folding kinetics at ϕ c can be quantitatively mapped onto confinement in a volume-fraction-dependent spherical pore with radius R s ≈ (4π/3ϕ c ) 1/3 R c ( R c is the radius of the crowding particles) as long as \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \setlength{\oddsidemargin}{-69pt} \begin{document} \begin{equation*}{\varphi}_{{\mathrm{c}}}{\leq}{\varphi}_{{\mathrm{c}}}^{*}\end{equation*}\end{document} . We show that the extent of native state stabilization at finite ϕ c is comparable with that in a spherical pore. In both situations, rate enhancement is due to destabilization of the denatured states with respect to ϕ c = 0.

The mechanism of denaturation of proteins by urea is explored by using all-atom microseconds molecular dynamics simulations of hen lysozyme generated on BlueGene/L. Accumulation of urea around lysozyme shows that water molecules are expelled from the first hydration shell of the protein. We observe a 2-stage penetration of the protein, with urea penetrating the hydrophobic core before water, forming a "dry globule." The direct dispersion interaction between urea and the protein backbone and side chains is stronger than for water, which gives rise to the intrusion of urea into the protein interior and to urea's preferential binding to all regions of the protein. This is augmented by preferential hydrogen bond formation between the urea carbonyl and the backbone amides that contributes to the breaking of intrabackbone hydrogen bonds. Our study supports the "direct interaction mechanism" whereby urea has a stronger dispersion interaction with protein than water.