Theses and Dissertations from UMD
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Item PARAMETERIZATION OF THE CHARMM LIPID FORCE FIELD AND APPLICATIONS TO MEMBRANE MODELING(2022) Yu, Yalun; Klauda, Jeffery B.; Biophysics (BIPH); Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)Computational modeling of lipids at the atomistic level provides insights into the chemical physics of biological membranes and opens the possibility to model membrane-protein interactions. This dissertation presents contributions to the CHARMM/Drude family of lipid force fields and applications of the CHARMM36 lipid force field to model membranes.Long-range Lennard-Jones interactions are critical for membrane simulations but were excluded from the CHARMM lipid force field for historical reasons. Re-parameterization of the CHARMM36 (C36) lipid force field for phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, and ether lipids is performed to incorporate these interactions through the Lennard-Jones particle-mesh Ewald (LJ-PME) method. The resulting force field is denoted C36/LJ-PME. C36/LJ-PME is in excellent agreement with experimental structure data for lipid bilayers and reproduces the experimental compression isotherm of monolayers. A semi-automated protocol is developed and used during this parameterization and significantly accelerates the whole process. The same protocol is used for the optimization of the Drude polarizable lipid force field. The optimization of this force field focuses on the structural and mechanical properties of bilayers and ab initio results of model compounds representing the lipid headgroup. Long-range dispersion interactions are incorporated into the force field as well. The resulting force field is validated against more structural and dynamic properties of bilayers and the compression isotherm of monolayers and demonstrates significant improvements over the past versions of the force field. In addition to these fully atomistic models, this dissertation also discusses the update to the CHARMM36 united atom chain model. Both the original model (C36UA) and the revised model (C36UAr) adopt the all-atom C36 lipid force field parameters for the headgroup and a united atom representation for the chain. The update focuses on the Lennard-Jones parameters of the hydrocarbon chain and related dihedrals. Bulk liquid properties (density, heat of vaporization, isothermal compressibility, and diffusion constant) of linear alkanes and alkenes and ab initio torsional scans are used as initial fitting targets. Bilayer surface area is used to fine-tune the dihedral parameters. Bilayer simulations of various headgroups and tails using C36UAr demonstrate significant improvements over C36UA from a structural perspective. The last part of this dissertation presents the applications of the C36 lipid force field. The inner membrane of Pseudomonas aeruginosa (P. aeruginosa) is modeled in two modes (planktonic and biofilm) to study the influence of lipid composition on bilayer structural and mechanical properties. The hydrophobic thicknesses of the model membrane agree with the P. aeruginosa transmembrane proteins in the Orientations of Proteins in Membranes (OPM) database. Symmetric and asymmetric models for the Arabidopsis thaliana plasma membrane are modeled. Molecular dynamics (MD) simulations indicate that the outer leaflet is more rigid and tightly packed to the inner leaflet. The interplay between glycolipids and sterols is found to be critical in lipid clustering and a possible mechanism for lipid phase separation has been proposed.Item Breast Cancer Type 1 Susceptibility Protein is a Critical Regulator of Skeletal Muscle Lipid Metabolism(2013) Jackson, Kathryn Campbell; Spangenburg, Espen E; Kinesiology; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)This dissertation research consists of three investigations in an effort to determine how circulating estrogens affect skeletal muscle lipid metabolism. Loss of circulating estrogens results in significant increases in visceral fat mass and intramuscular lipids (IMCL). These increases in lipid storage are strongly associated with an elevated risk of developing type 2 diabetes. The first investigation examined how the loss of circulating estrogens alters skeletal muscle metabolic function. Ovariectomy (OVX) resulted in significantly higher visceral fat mass and fatty acid sarcolemmal transporter content, which corresponded with elevated IMCL. Skeletal muscle in the OVX group exhibited lower acyl carnitine species suggesting impaired lipid flux through the mitochondria. Lastly, mitochondrial oxygen consumption rates were impaired in OVX skeletal muscle fibers. The results from this study gave rise to a search to identify an estrogen- sensitive mechanism that regulated lipid transport into the mitochondria. Study two determined for the first time that the BRCA1 protein, which is encoded by an estrogen-sensitive gene, is present and functions as an integral regulator of lipid metabolism in skeletal muscle. Specifically, BRCA1 binds to acetyl CoA carboxylase in response to acute exercise. The in vitro induction of decreases in BRCA1 expression resulted in higher IMCL content, reduced mitochondrial oxygen consumption rates, and elevated reactive oxygen species production. Surprisingly, no differences in BRCA1 content were detected between males and females. In the final study, an inducible, skeletal-muscle specific, BRCA1 KO mouse was developed. Ablation of BRCA1 in skeletal muscle resulted in exercise intolerance and the development of kyphosis. Contrary to our hypothesis, loss of functional BRCA1 in skeletal muscle attenuated the negative metabolic consequences of chronic high fat diet exposure. Collectively, these data provide strong rationale that BRCA1 is an important regulator of skeletal muscle metabolic function and further provide evidence that BRCA1 function is critical in multiple tissues across the body.Item Denovo synthesized fatty acids as regulators of milk fat synthesis(2011) Vyas, Diwakar; Erdman, Richard A; Animal Sciences; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)The objectives of the dissertation research were to determine the role of denovo synthesized fatty acids (DNFA) in the regulation of milk fat synthesis. Milk fat responses to increasing amounts of short- and medium-chain fatty acids (SMCFA), added in the proportion as synthesized denovo, were studied in lactating dairy cows. The results showed a significant linear increase in milk fat concentration with SMCFA supplementation. However, milk fat yield was similar for all treatments. A subsequent study was aimed at increasing the availability of SMCFA during trans-10, cis-12 CLA-induced milk fat depression (MFD) in lactating dairy cows to determine whether SMCFA can rescue part of CLA-induced MFD. Post-ruminal infusion of butterfat (BF) was used as a source of SMCFA. The BF treatment was compared to a mixture of fats containing only the long-chain FA (LCFA) with or without trans-10, cis-12 CLA infusion. Milk fat content and yield were significantly reduced with trans-10, cis-12 CLA. However, increased availability of SMCFA with BF infusion had no effects on milk fat yield and concentration. Trans-10, cis-12 CLA significantly reduced the mRNA expression of transcription factor SREBP-1c along with its downstream targets including ACC,FASN, LPL, SCD and AGPAT. The increased availability of SMCFA had no effect on either lipogenic gene or protein expression suggesting that nutritional manipulation was not sufficient to rescue trans-10, cis-12 CLA-induced MFD. Finally, the effects of combination of a Rosiglitazone (ROSI), a PPAR-γ agonist, and trans-10, cis-12 CLA were examined on mammary and hepatic lipogenesis in lactating mice. Mammary lipogenesis was significantly reduced with trans-10, cis-12 CLA, reducing the milk fat content and mRNA expression of lipogenic transcription factors SREBP1-c and PPAR- γ. Trans-10, cis-12 CLA significantly increased hepatic lipid accumulation, while the mRNA expression of SREBP1-c and PPAR- γ were not altered. On the contrary, ROSI had no effects on mammary lipogenesis. However, ROSI significantly rescued trans-10, cis-12 CLA-induced hepatic steatosis.