Biomedical subjects

B A Shoemaker

Publications and source records attributed to B A Shoemaker.

4 recordsLinked to original sources

PubMed2000

Speeding molecular recognition by using the folding funnel: the fly-casting mechanism.

Protein folding and binding are kindred processes. Many proteins in the cell are unfolded, so folding and function are coupled. This paper investigates how binding kinetics is influenced by the folding of a protein. We find that a relatively unstructured protein molecule can have a greater capture radius for a specific binding site than the folded state with its restricted conformational freedom. In this scenario of binding, the unfolded state binds weakly at a relatively large distance followed by folding as the protein approaches the binding site: the "fly-casting mechanism." We illustrate this scenario with the hypothetical kinetics of binding a single repressor molecule to a DNA site and find that the binding rate can be significantly enhanced over the rate of binding of a fully folded protein.

Kinetics↗

PubMed1999

Exploring structures in protein folding funnels with free energy functionals: the denatured ensemble.

We discuss the formulation of free energy functionals that describe the formation of structure in partially folded proteins. These free energy functionals take into account the inhomogeneous nature of contact energies, chain entropy and cooperative contributions reflecting the many body character of some folding forces like hydrophobicity, but do not directly account for non-native contacts because they assume the validity of the minimal frustration principle. We show how the free energy functionals can be used to interpret experiments on partially folded proteins that probe the fractional occupancy of specific local structures. In particular, we study the hydrogen protection factors in lysozyme studied in transient experiments by Gladwin and Evans and by Nash and Jonas using equilibrium pressure denaturation and the NMR order parameters measured by Dobson and Kim for the homologous protein alpha-lactalbumin.

Animals↗

PubMed1999

Exploring structures in protein folding funnels with free energy functionals: the transition state ensemble.

We use free energy functionals that account for the partial ordering of residues in the transition state ensemble to characterize the free energy surfaces for fast folding proteins. We concentrate on chymotrypsin inhibitor and lambda-repressor. We show how the explicit cooperativity that can arise from many body forces, such as side-chain ordering or hydrophobic surface burial, determines the crossover from folding with a large delocalized nucleus and the specific small classical nucleus of the type envisioned in nucleation growth scenarios. We compare the structural correlations present in the transition state ensemble obtained from free energy functionals with those inferred from experiment using extrathermodynamic free energy relations for folding time obtained via protein engineering kinetics experiments. We also use the free energy functionals to examine both the size of barriers and multidimensional representations of the free energy profiles in order to address the question of appropriate reaction coordinates for folding.

DNA-Binding Proteins↗

PubMed1997

Structural correlations in protein folding funnels.

While the overall energy landscape of a foldable protein can be described by means of a few parameters characterizing its statistical topography, specific energetic terms subtly bias the representative structures giving rise to residue pair correlations as in a liquid. We use a free energy functional incorporating an inhomogeneous pair contact energy along with a contact formation entropy and a cooperativity contribution to determine residue-specific contact probabilities in the denatured state and the transition state ensemble. The predicted "hot residues" for the theoretical transition state ensemble reasonably agree with experiment for chymotrypsin inhibitor 2, and generally a strong correlation exists with the measured kinetic effects of mutating residues not involved in highly solvent-exposed regions.

Amino Acids↗