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Biomedical subjects

R Stephen Berry

Publications and source records attributed to R Stephen Berry.

23 records · Page 2Linked to original sources
PubMed2003

Large-scale context in protein folding: villin headpiece.

The villin headpiece folds autonomously in vitro forming three alpha-helical regions. Local propensities, however, strongly disfavor the formation of the C-terminal helix because most native residue pairs in that helix are hydrophobic/polar mismatches. Even the N-terminal helix is unfavored according to the AGADIR criterion. Our coarse-grained ab initio simulations reveal three-body correlations in which hydrophobic residues position to protect amide-carbonyl hydrogen bonds from attack by water, thus inducing the growth of the C-terminal helix and guiding the folding process. Similar correlations are also found in all-atom simulations with an implicit solvent model that accurately reproduces the results of simulations with explicit solvent molecules. The correlations establish a large-scale, many-body context that may be probed experimentally by introducing mutations of certain nonobvious residues that reside outside the native hydrophobic core but that are predicted to affect the folding rates and dynamics dramatically.

Alanine↗
PubMed2002

Distinguishing foldable proteins from nonfolders: when and how do they differ?

When a denatured polypeptide is put into refolding conditions, it undergoes conformational changes on a variety of times scales. We set out here to distinguish the fast events that promote productive folding from other processes that may be generic to any non-folding polypeptide. We have apply an ab initio folding algorithm to model the folding of various proteins and their compositionally identical, random-sequence analogues. In the earliest stages, proteins and their scrambled-sequence counterparts undergo indistinguishable reductions in the extent to which they explore conformation space. For both polypeptides, an early contraction occurs but does not involve the formation of a distinct intermediate. Following this phase, however, the naturally-occurring sequences are distinguished by an increase in the formation of three-body correlations wherein a hydrophobic group desolvates and protects an intra-molecular hydrogen bond. These correlations are manifested in a mild but measurable reduction of the accessible configuration space beyond that of the random-sequence peptides, and portend the folding to the native structure. Hence, early events reflect a generic response of the denatured ensemble to a change in solvent condition, but the wild-type sequence develops additional correlations as its structure evolves that can reveal the protein's foldability.

Algorithms↗
PubMed2002

Entropic benefit of a cross-link in protein association.

We introduce a method to estimate the loss of configurational entropy upon insertion of a cross-link to a dimeric system. First, a clear distinction is established between the loss of entropy upon tethering and binding, two quantities that are often considered to be equivalent. By comparing the probability distribution of the center-to-center distances for untethered and cross-linked versions, we are able to calculate the loss of translational entropy upon cross-linking. The distribution function for the untethered helices is calculated from the probability that a given helix is closer to its partner than to all other helices, the "Nearest Neighbor" method. This method requires no assumptions about the nature of the solvent, and hence resolves difficulties normally associated with calculations for systems in liquids. Analysis of the restriction of angular freedom upon tethering indicates that the loss of rotational entropy is negligible. The method is applied in the context of the folding of a ten turn helical coiled coil with the tether modeled as a Gaussian chain or a flexible amino acid chain. After correcting for loop closure entropy in the docked state, we estimate the introduction of a six-residue tether in the coiled coil results in an effective concentration of the chain to be about 4 or 100 mM, depending upon whether the helices are denatured or pre-folded prior to their association. Thus, tethering results in significant stabilization for systems with millimolar or stronger dissociation constants.

Dimerization↗
PubMed2002

Variational theory for thermodynamics of thermal waves.

We discuss description of macroscopic representations of thermal fields with finite signal speed by composite variational principles involving suitably constructed potentials along with original physical variables. A variational formulation for a given vector field treats all field equations as constraints that are linked by Lagrange multipliers to the given kinetic potential. We focus on the example of simple hyperbolic heat transfer, but also stress that the approach can be easily extended to the coupled transfer of heat, mass, and electric charge. With our approach, various representations may be obtained for physical fields in terms of potentials (gradient or non-gradient representations). Corresponding Lagrangian and Hamiltonian formalism can be developed. Symmetry principles yield components of the energy-momentum tensor for the given kinetic potential. The limiting reversible case appears as a special yet suitable reference frame to describe irreversible phenomena. With the conservation laws resulting from the least action principle and the Gibbs equation, the variational scheme of nonequilibrium thermodynamics follows. Its main property is abandoning the assumption of local thermal equilibrium.

Journal Article↗