On the role of entropy in the protein folding process

A protein's ultimate function and activity is determined by the unique three-dimensional structure taken by the folding process. Protein malfunction due to misfolding is the culprit of many clinical disorders, such as abnormal protein aggregations. This leads to neurodegenerative disorders likeHuntington's and Alzheimer's disease. We focus on a subset of the folding problem, exploring the role and effects of entropy on the process of protein folding. Four major concepts and models are developed and each pertains to a specfic aspect of the folding process: entropic forces, conformationalstates under crowding, aggregation, and macrostate kinetics from microstate trajectories.The exclusive focus on entropy is well-suited for crowding studies, as many interactions are nonspecific. We show how a stabilizing entropic force can arise purely from the motion of crowders in solution. In addition we are able to make a a quantitative prediction of the crowding effect with animplicit crowding approximation using an aspherical scaled-particle theory.In order to investigate the effects of aggregation, we derive a new operator expansion method to solve the Ising/Potts model with external fields over an arbitrary graph. Here the external fields are representative of the entropic forces. We show that this method reduces the problem of calculating the partition function to the solution of recursion relations.Many of the methods employed are coarse-grained approximations. As such, it is useful to have a viable method for extracting macrostate information from time series data. We develop a method to cluster the microstates into physically meaningful macrostates by grouping similar relaxation times from a transition matrix.Overall, the studied topics allow us to understand deeper the complicated process involving proteins.Ph.D., Physics -- Drexel University, 201

Non-specific Interactions Between Macromolecular Solutes in Concentrated Solution: Physico-Chemical Manifestations and Biochemical Consequences

A general thermodynamic formulation of the effect of hard and soft non-specific intermolecular interactions upon reaction equilibria is summarized. A highly simplified quantitative model for non-specific intermolecular interaction is introduced. This model is used to illustrate how the magnitudes of attractive and repulsive components of the overall intermolecular interaction, and the balance between them, influence the concentration-dependent properties of a highly concentrated solution of a single macromolecular solute. The properties calculated using the results of computer simulation and an approximate analytical model are found to agree qualitatively with the results of experimental measurements on protein solutions over a broad range of concentration

Family history of cancer as a risk factor for second malignancies after Hodgkin's lymphoma

This study estimated the risk of second primary malignancies after Hodgkin's lymphoma (HL) in relation to family history of cancer, age at diagnosis and latency, among 6946 patients treated for HL in Sweden in 1965–1995 identified through the Swedish Cancer Register (SCR). First-degree relatives (FDRs) to the HL patients and their malignancies were then ascertained together with their malignancies through the Multi-Generation Registry and SCR. The HL patient cohort was stratified on the number of FDRs with cancer, and standardised incidence ratios (SIRs) of developing SM were analysed. In the HL cohort, 781 SM were observed 1 year or longer after HL diagnosis. The risk for developing SM increased with the number of FDRs with cancer, SIRs being 2.26, 3.01, and 3.45 with 0, 1, or ⩾2 FDRs with cancer, respectively. Hodgkin's lymphoma long-term survivors treated at a young age with a family history of cancer carry an increased risk for developing SM and may represent a subgroup where standardised screening for the most common cancer sites could be offered in a stringent surveillance programme

Animal foods, protein, calcium and prostate cancer risk: the European Prospective Investigation into Cancer and Nutrition

We examined consumption of animal foods, protein and calcium in relation to risk of prostate cancer among 142 251 men in the European Prospective Investigation into Cancer and Nutrition. Associations were examined using Cox regression, stratified by recruitment centre and adjusted for height, weight, education, marital status and energy intake. After an average of 8.7 years of follow-up, there were 2727 incident cases of prostate cancer, of which 1131 were known to be localised and 541 advanced-stage disease. A high intake of dairy protein was associated with an increased risk, with a hazard ratio for the top versus the bottom fifth of intake of 1.22 (95% confidence interval (CI): 1.07–1.41, Ptrend=0.02). After calibration to allow for measurement error, we estimated that a 35-g day−1 increase in consumption of dairy protein was associated with an increase in the risk of prostate cancer of 32% (95% CI: 1–72%, Ptrend=0.04). Calcium from dairy products was also positively associated with risk, but not calcium from other foods. The results support the hypothesis that a high intake of protein or calcium from dairy products may increase the risk for prostate cancer

Singular value decomposition of the radial distribution function for hard sphere and square well potentials.

We compute the singular value decomposition of the radial distribution function g(r) for hard sphere, and square well solutions. We find that g(r) decomposes into a small set of basis vectors allowing for an extremely accurate representation at all interpolated densities and potential strengths. In addition, we find that the coefficient vectors describing the magnitude of each basis vector are well described by a low-order polynomial. We provide a program to calculate g(r) in this compact representation for the investigated parameter range

Parameter space of the SW, <i>λ</i> = 1.25 potential.

<p>The vertical and horizontal dashed lines indicate the variation for SW and SW respectively. The cross indicates the point at which the well depth was varied SW, and the shaded region indicates the two parameter region explored SW. The vertical axis is plotted in for comparison to known coexistence curves. As a reference, we show the liquid-vapor coexistence curve as a solid line, with a red dot at the critical point, , , from Vega <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0075792#pone.0075792-Vega1" target="_blank">[24]</a> and the coexistence curve determined via Gibbs-Duhem integration <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0075792#pone.0075792-Kofke1" target="_blank">[29]</a>.</p

Five most dominant coefficient vectors for the hard sphere system HS.

<p>The polynomial fits to the vectors are shown as dashed lines.</p