Early stages of misfolding of PAP248-286 at two different pH values: An insight from molecular dynamics simulations

PAP248-286 peptides, which are highly abundant in human semen, aggregate and form amyloid fibrils that enhance HIV infection. Previous experimental studies have shown that the infection-promoting activity of PAP248-286 begins to increase well before amyloid formation takes place and that pH plays a key role in the enhancement of PAP248-286-related infection. Hence, understanding the early stages of misfolding of the PAP2482-86 peptide is crucial. To this end, we have performed 60 independent MD simulations for a total of 24 µs at two different pH values (4.2 and 7.2). Our data shows that early stages of misfolding of the PAP248-286 peptide is a multistage process and that the first step of the process is a transition from an "I-shaped" structure to a "U-shaped" structure. We further observed that the structure of PAP248-286 at the two different pH values shows significantly different features. At pH 4.2, the peptide has less intra-molecular H-bonds and a reduced α-helical content than at pH 7.2. Moreover, differences in intra-peptide residues contacts are also observed at the two pH values. Finally, free energy landscape analysis shows that there are more local minima in the energy surface of the peptide at pH 7.2 than at pH 4.2. Overall, the present study elucidates the early stages of misfolding of the PAP248-286 peptide at the atomic level, thus possibly opening new avenues in structure-based drug discovery against HIV infection

Self-Consistent Description of Vapor-Liquid Interface in Ionic Fluids

Inhomogeneity of ion correlation widely exists in many physicochemical, soft matter, and biological systems. Here, we apply the modified Gaussian renormalized fluctuation theory to study the classic example of the vapor-liquid interface of ionic fluids. The ion correlation is decomposed into a short-range contribution associated with the local electrostatic environment and a long-range contribution accounting for the spatially varying ionic strength and dielectric permittivity. For symmetric salt, both the coexistence curve and the interfacial tension predicted by our theory are in quantitative agreement with simulation data reported in the literature. Furthermore, we provide the first theoretical prediction of interfacial structure for asymmetric salt, highlighting the importance of capturing local charge separation

Fast Algorithms for Online Stochastic Convex Programming

We introduce the online stochastic Convex Programming (CP) problem, a very general version of stochastic online problems which allows arbitrary concave objectives and convex feasibility constraints. Many well-studied problems like online stochastic packing and covering, online stochastic matching with concave returns, etc. form a special case of online stochastic CP. We present fast algorithms for these problems, which achieve near-optimal regret guarantees for both the i.i.d. and the random permutation models of stochastic inputs. When applied to the special case online packing, our ideas yield a simpler and faster primal-dual algorithm for this well studied problem, which achieves the optimal competitive ratio. Our techniques make explicit the connection of primal-dual paradigm and online learning to online stochastic CP.Comment: To appear in SODA 201

The binding of Alzheimer’s amyloid beta peptides with a candidate drug molecule, 12-crown-4, and a biological membrane : insight from molecular dynamics simulations.

Doctor of Philosophy in Pharmaceutical Chemistry. University of KwaZulu-Natal. Durban, 2018.Abstract available in PDF file

Elucidating the mechanics of clathrin-mediated endocytosis

Clathrin-mediated endocytosis (CME) is a key metabolic pathway that plays a central role in the delivery of nutrients and drug carriers into cells. In this study, we model the interactions of lipid membranes with different types of protein scaffolds and active forces to provide mechanistic insights into CME. To this end, we develop and employ an extended theoretical framework of lipid membranes that entertains spatial heterogeneity and local anisotropy that could arise from membrane–protein interactions. We show that a departure from homogeneity and isotropy can lead to a variable surface tension field, conventionally assumed to be a constant parameter. We model the impact of resting tension in a cell and discuss its consequences on the minimal protein machinery needed to complete vesicle formation. Based on our quantitative model and findings, we highlight the physical principles that unify CME in apparently distinct yeast and mammalian cells