Jamming effects in glasses and biopolymers

In this dissertation, jamming effects in highly packed systems are studied in two specific materials: glasses and biopolymers in cellular environments. Suspensions consisting of highly charged colloids, which are well-known glass-forming systems, are investigated using molecular dynamics simulations in order to test Random First Order Transition (RFOT) theory. I found that there is a critical volume fraction at which ergodic-to-nonergodic transitions for three dynamic observables take place in accordance with RFOT. Based on numerical observations, it is also proposed that the dynamic heterogeneity can be attributed to the violation of law of large numbers. In addition, the bond orientational order of colloidal suspensions and soft-spheres is discussed in the context of liquid-glass transitions. The response of biopolymers to a crowded environment is another interesting issue because 20-40% volume of a cell is occupied by various cellular components such as ribosomes and proteins in vivo. In this work, using low-friction langevin dynamics simulations with explicit crowding particles, I examined the conformational change of biopolymers in the presence of crowders of various sizes and shapes. The simulation results reveal that cylindrical crowders induce much greater compaction of the polymers than spherical ones at low volume fractions and the stronger crowding effects disappear at higher volume fractions due to local nematic ordering of cylindrical particles. The reduction in the size of polymer is even more dramatic in a mixture of spherical and cylindrical shapes because of cooperative crowding effects explained by the phase separation of spheres and rodlike particles. Finally, the crowding effects of cellular components on bacterial chromosomes are estimated using a mixture of spherical crowders with the composition found in bacterial cytoplasms

Poly(L-histidine)-tagged 5-aminolevulinic acid prodrugs: new photosensitizing precursors of protoporphyrin IX for photodynamic colon cancer therapy

Renjith P Johnson,1* Chung-Wook Chung,2* Young-Il Jeong,2 Dae Hwan Kang,2 Hongsuk Suh,3 Il Kim,11WCU Centre for Synthetic Polymer Bioconjugate Hybrid Materials, Department of Polymer Science and Engineering, Pusan National University, Pusan, 2National Research and Development Center for Hepatobiliary Cancer, Pusan National University, Yangsan Hospital, Yangsan, Gyeongnam, 3Department of Chemistry and Chemistry Institute for Functional Materials, Pusan National University, Pusan, Korea*These authors contributed equally to this workBackground: 5-Aminolevulinic acid (ALA) and its derivatives have been widely used in photodynamic therapy. The main drawback associated with ALA-based photodynamic therapy (ALA-PDT) and ALA fluorescence diagnosis results from the hydrophilic nature of ALA and lack of selectivity for tumor versus nontumor cells. The application of certain triggers, such as pH, into conventional sensitizers for controllable 1O2 release is a promising strategy for tumor-targeted treatment.Methods: A series of pH-sensitive ALA-poly(L-histidine) [p(L-His)n] prodrugs were synthesized via ring opening polymerization of 1-benzyl-N-carboxy-L-histidine anhydride initiated by the amine hydrochloride group of ALA itself. As an alternative to ALA for PDT, the synthesized prodrugs were used to treat a cultured human colon cancer HCT116 cell line under different pH conditions. The effect of ALA-p(L-His)n derivatives was evaluated by monitoring the fluorescence intensity of protoporphyrin IX, and measuring the cell survival rate after suitable light irradiation.Results: The cytotoxicity and dark toxicity of ALA and synthesized ALA-p(L-His) derivatives in HEK293T and HCT116 cells in the absence of light at pH 7.4 and 6.8 shows that the cell viability was relatively higher than 100%. ALA-p(L-His)n showed high phototoxicity and selectivity in different pH conditions compared with ALA alone. Because the length of the histidine chain increases in the ALA-p(L-His)n prodrugs, the PDT effect was found to be more powerful. In particular, high phototoxicity was observed when the cells were treated with ALA-p(L-His)15, compared with treatment using ALA alone.Conclusion: The newly synthesized ALA-p(L-His)n derivatives are an effective alternative to ALA for enhancing protoporphyrin IX production and the selectivity of the phototoxic effect in tumor cells.Keywords: 5-aminolevulinic acid, photodynamic therapy, poly(L-histidine), bioconjugate, cancer cell

New solvation free energy function comprising intermolecular solvation and intramolecular self-solvation terms

Abstract Solvation free energy is a fundamental thermodynamic quantity that should be determined to estimate various physicochemical properties of a molecule and the desolvation cost for its binding to macromolecular receptors. Here, we propose a new solvation free energy function through the improvement of the solvent-contact model, and test its applicability in estimating the solvation free energies of organic molecules with varying sizes and shapes. This new solvation free energy function is constructed by combining the existing solute-solvent interaction term with the self-solvation term that reflects the effects of intramolecular interactions on solvation. Four kinds of atomic parameters should be determined in this solvation model: atomic fragmental volume, maximum atomic occupancy, atomic solvation, and atomic self-solvation parameters. All of these parameters for total 37 atom types are optimized by the operation of a standard genetic algorithm in such a way to minimize the difference between the experimental solvation free energies and those calculated by the solvation free energy function for 362 organic molecules. The solvation free energies estimated from the new solvation model compare well with the experimental results with the associated squared correlation coefficients of 0.88 and 0.85 for training and test sets, respectively. The present solvation model is thus expected to be useful for estimating the solvation free energies of organic molecules.</p

Computational Prediction of Molecular Hydration Entropy with Hybrid Scaled Particle Theory and Free-Energy Perturbation Method

Despite the importance of the knowledge of molecular hydration entropy (Δ<i>S</i>_hyd) in chemical and biological processes, the exact calculation of Δ<i><i>S</i></i>_hyd is very difficult, because of the complexity in solute–water interactions. Although free-energy perturbation (FEP) methods have been employed quite widely in the literature, the poor convergent behavior of the van der Waals interaction term in the potential function limited the accuracy and robustness. In this study, we propose a new method for estimating Δ<i><i>S</i></i>_hyd by means of combining the FEP approach and the scaled particle theory (or information theory) to separately calculate the electrostatic solute–water interaction term (Δ<i><i>S</i></i>_elec) and the hydrophobic contribution approximated by the cavity formation entropy (Δ<i><i>S</i></i>_cav), respectively. Decomposition of Δ<i><i>S</i></i>_hyd into Δ<i><i>S</i></i>_cav and Δ<i><i>S</i></i>_elec terms is found to be very effective with a substantial accuracy enhancement in Δ<i><i>S</i></i>_hyd estimation, when compared to the conventional full FEP calculations. Δ<i><i>S</i></i>_cav appears to dominate over Δ<i><i>S</i></i>_elec in magnitude, even in the case of polar solutes, implying that the major contribution to the entropic cost for hydration comes from the formation of a solvent-excluded volume. Our hybrid scaled particle theory and FEP method is thus found to enhance the accuracy of Δ<i><i>S</i></i>_hyd prediction by effectively complementing the conventional full FEP method

Lanosterol Disrupts Aggregation of Human γD-Crystallin by Binding to the Hydrophobic Dimerization Interface

Cataracts are a leading cause of vision impairment, which stem from the misfolding and aggregation of crystallins in the eye lens. Despite its prevalence and severity, the detailed mechanism by which misfolded crystallins aggregate into cataracts remains elusive. Recently, <i>in vitro</i> and <i>in vivo</i> experiments demonstrated that lanosterol, a steroid-type compound found in human and animal eyes, can not only prevent cataract formation but also reverse the formation. Inspired by these experimental observations, we investigate the preventive activity of lanosterol in the aggregate formation of human γD-crystallins (HγD-Crys) using all atom molecular dynamics (MD) simulation and free energy perturbation (FEP) techniques. Our results reveal that lanosterol preferentially binds to the HγD-Crys hydrophobic dimerization interface, in particular, to the structured C-terminus (near residues 135–165) with a stronger binding affinity than the unfolded N-terminus. Furthermore, we observe that the C-terminal binding is more favorable than lanosterol self-aggregation, further attesting to lanosterol’s efficacy. Finally, we compare the binding free energy of lanosterol with cholesterol using alchemical transformation and discuss the possible correlation of the molecular geometry of steroids with binding affinity

Unexpected Swelling of Stiff DNA in a Polydisperse Crowded Environment

We investigate the conformations of DNA-like stiff chains, characterized by contour length (<i>L</i>) and persistence length (<i>l</i>_p), in a variety of crowded environments containing monodisperse soft spherical (SS) and spherocylindrical (SC) particles, a mixture of SS and SC, and a milieu mimicking the composition of proteins in the Escherichia coli cytoplasm. The stiff chain, whose size modestly increases in SS crowders up to ϕ ≈ 0.1, is considerably more compact at low volume fractions (ϕ ≤ 0.2) in monodisperse SC particles than in a medium containing SS particles. A 1:1 mixture of SS and SC crowders induces greater chain compaction than the pure SS or SC crowders at the same ϕ, with the effect being highly nonadditive. We also discover a counterintuitive result that the polydisperse crowding environment, mimicking the composition of a cell lysate, swells the DNA-like polymer, which is in stark contrast to the size reduction of flexible polymers in the same milieu. Trapping of the stiff chain in a fluctuating tube-like environment created by large-sized crowders explains the dramatic increase in size and persistence length of the stiff chain. In the polydisperse medium, mimicking the cellular environment, the size of the DNA (or related RNA) is determined by <i>L</i>/<i>l</i>_p. At low <i>L</i>/<i>l</i>_p, the size of the polymer is unaffected, whereas there is a dramatic swelling at an intermediate value of <i>L</i>/<i>l</i>_p. We use these results to provide insights into recent experiments on crowding effects on RNA and also make testable predictions