Physics-based modeling for RNA folding stability and kinetics

[ACCESS RESTRICTED TO THE UNIVERSITY OF MISSOURI--COLUMBIA AT REQUEST OF AUTHOR.] RNA (Ribonucleic acid) molecules play a variety of crucial roles in cellular functions at the level of transcription, translation and gene regulation. RNA functions are often tied to its 3D structure and dynamics. To quantitatively understand the relationship between RNA functions and its 3D structures and kinetics, we need a computational model for RNA folding. My research involves several components about theoretical and computational modeling of RNA folding. To provide a user friendly tool for RNA biologists, we developed a fully-automated web interface and software for RNA 2D and 3D structure prediction from nucleotide sequence. The software and webserver is based on the Vfold2D and Vfold3D models developed by our lab. A key issue in the current RNA structure prediction methods is modeling of loop structures. In Vfold2D model, we use a physics-based coarse-grained representation for RNA conformations which samples all the possible loop conformations in 3D space to calculate the loop entropy and free energy parameters. For the 3D structure prediction, we use a template-based method to assemble RNA 3D structures from motifs. In a cell, an RNA folds as it is transcribed and the process is kinetically controlled. To predict RNA folding kinetics in a cell, based on a helix-based rate model, we developed a new method for sampling cotranscriptional RNA conformation ensemble and prediction of cotranscriptional folding kinetics. Applications to E. Coli. SRP RNA and pbuE riboswitch indicate that the model may provide reliable predictions for the cotranscriptional folding pathways and population kinetics. For E. Coli. SRP RNA, the predicted population kinetics and the folding pathway are consistent with those from profiles in the recent cotranscriptional SHAPE-seq experiments. For the pbuE riboswitch, the model predicts the transcriptional termination efficiency as a function of the force. The theoretical results show (a) a force-induced transition from the aptamer (antiterminator) to the terminator structure and (b) the different folding pathways for the riboswitch with and without the ligand (adenine). More Specifically, without adenine, the aptamer structure emerges as a short-lived kinetic transient state instead of a thermodynamically stable intermediate state. Furthermore, from the predicted extension-time curves, the model identifies a series of conformational switches in the pulling process, where the predicted relative residence times for the different structures are in accordance with the experimental data. The model may provide a new tool for quantitative predictions of cotranscriptional folding kinetics and results can offer useful insights into cotranscriptional folding-related RNA functions such as regulation of gene expression with riboswitches. One of the major roadblocks for RNA structure prediction is the effects of ion concentrations and loop sequence. However, most structure prediction models do not explicitly consider ion and loop sequence effects. RNA hairpin is one the most fundamental motifs in RNA structures. To predict the ion and loop sequence effects, we developed a novel integrated computational approach by combining 2D and 3D folding models with an ion electrostatic model. We demonstrate that the approach not only predicts folding stabilities that quantitatively agree with experiment results but also provides detailed structural and energetic insights into the hairpin stability. The approach developed here is general and can be directly applied to treat general RNA systems.Includes bibliographical reference

A Peritumorally Injected Immunomodulating Adjuvant Elicits Robust and Safe Metalloimmunotherapy against Solid Tumors

Clinical immunotherapy of solid tumors elicits durable responses only in a minority of patients, largely due to the highly immunosuppressive tumor microenvironment (TME). Although rational combinations of vaccine adjuvants with inflammatory cytokines or immune agonists that relieve immunosuppression represent an appealing therapeutic strategy against solid tumors, there are unavoidable nonspecific toxicities due to the pleiotropy of cytokines and undesired activation of off-target cells. Herein, a Zn2+ doped layered double hydroxide (Zn-LDH) based immunomodulating adjuvant, which not only relieves immunosuppression but also elicits robust antitumor immunity, is reported. Peritumorally injected Zn-LDH sustainably neutralizes acidic TME and releases abundant Zn2+, promoting a pro-inflammatory network composed of M1-tumor-associated macrophages, cytotoxic T cells, and natural-killer cells. Moreover, the Zn-LDH internalized by tumor cells effectively disrupts endo-/lysosomes to block autophagy and induces mitochondrial damage, and the released Zn2+ activates the cGas-STING signaling pathway to induce immunogenic cell death, which further promotes the release of tumor-associated antigens to induce antigen-specific cytotoxic T lymphocytes. Unprecedentedly, merely injection of Zn-LDH adjuvant, without using any cytotoxic inflammatory cytokines or immune agonists, significantly inhibits the growth, recurrence, and metastasis of solid tumors in mice. This study provides a rational bottom-up design of potent adjuvant for cancer metalloimmunotherapy against solid tumors

A Peritumorally Injected Immunomodulating Adjuvant Elicits Robust and Safe Metalloimmunotherapy against Solid Tumors

Clinical immunotherapy of solid tumors elicits durable responses only in a minority of patients, largely due to the highly immunosuppressive tumor microenvironment (TME). Although rational combinations of vaccine adjuvants with inflammatory cytokines or immune agonists that relieve immunosuppression represent an appealing therapeutic strategy against solid tumors, there are unavoidable nonspecific toxicities due to the pleiotropy of cytokines and undesired activation of off-target cells. Herein, a Zn2+ doped layered double hydroxide (Zn-LDH) based immunomodulating adjuvant, which not only relieves immunosuppression but also elicits robust antitumor immunity, is reported. Peritumorally injected Zn-LDH sustainably neutralizes acidic TME and releases abundant Zn2+, promoting a pro-inflammatory network composed of M1-tumor-associated macrophages, cytotoxic T cells, and natural-killer cells. Moreover, the Zn-LDH internalized by tumor cells effectively disrupts endo-/lysosomes to block autophagy and induces mitochondrial damage, and the released Zn2+ activates the cGas-STING signaling pathway to induce immunogenic cell death, which further promotes the release of tumor-associated antigens to induce antigen-specific cytotoxic T lymphocytes. Unprecedentedly, merely injection of Zn-LDH adjuvant, without using any cytotoxic inflammatory cytokines or immune agonists, significantly inhibits the growth, recurrence, and metastasis of solid tumors in mice. This study provides a rational bottom-up design of potent adjuvant for cancer metalloimmunotherapy against solid tumors

An Efficient Strategy for Searching High Lattice Thermal Conductivity Materials

Searching for high thermal conductivity materials to efficiently conduct heat for various applications is a long-term endeavor. In 1973, Slack gave four rules for a material with high thermal conductivity, including low atomic mass, strong interatomic bonds, simple crystal structure, and low lattice anharmonicity. Comparing the thermal conductivities of 5 carbon allotropes carefully selected from the Carbon Allotrope Database, we found that a high symmetry operation number SO or a small atom number n in the primitive unit cell can significantly reduce the phonon–phonon scattering phase space. Based on SO and n, we comprehensively searched the Database of 803 carbon allotropes and found that the bcc-C6 allotrope has a high thermal conductivity owing to its high SO of 96 and small n of 6. The calculated lattice thermal conductivity of bcc-C6 can reach 2198 W/m K at room temperature if its atomic packing fraction equals that of diamond. Our findings indicate that high crystal symmetry can be employed as an efficient strategy to search for materials with high thermal conductivity

Thermal Transport in Quasi-1D van der Waals Crystal Ta₂Pd₃Se₈ Nanowires: Size and Length Dependence

Van der Waals (vdW) crystals with covalently bonded building blocks assembled together through vdW interactions have attracted tremendous attention recently because of their interesting properties and promising applications. Compared to the explosive research on two-dimensional (2D) vdW materials, quasi-one-dimensional (quasi-1D) vdW crystals have received considerably less attention, while they also present rich physics and engineering implications. Here we report on the thermal conductivity of exfoliated quasi-1D Ta₂Pd₃Se₈ vdW nanowires. Interestingly, even though the interatomic interactions along each molecular chain are much stronger than the interchain vdW interactions, the measured thermal conductivity still demonstrates a clear dependence on the cross-sectional size up to >110 nm. The results also reveal that partial ballistic phonon transport can persist over 13 μm at room temperature along the molecular chain direction, the longest experimentally observed ballistic transport distance with observable effects on thermal conductivity so far. First-principles calculations suggest that the ultralong ballistic phonon transport arises from the highly focused longitudinal phonons propagating along the molecular chains. These data help to understand phonon transport through quasi-1D vdW crystals, facilitating various applications of this class of materials