Simulations of proton transfer processes using reactive force fields

Within this thesis we presented the development of reactive force fields that are ca- pable to describe the dynamics of proton and hydrogen atom transfer processes. The presented implementation in CHARMM overcomes the limitation that bond break- ing and formation cannot be investigated by conventional classical MD simulations. Derived from high-level ab initio calculations this approach combines the accuracy of such calculations with the speed of MD simulations. The high-quality force fields of the prototype systems are comparable to high-level ab initio calculations in terms of structure and energy barriers. The PESs of proton transfer reactions are extremely sensitive with respect to the chemical environment. Nevertheless one is always able to classify the PT under investigation into symmetric and asymmetric PES. We de- veloped a series of parameter sets that are not only able to describe symmetric and asymmetric correctly but also can accommodate to different locations of energetic minima and barriers. The chosen three-dimensional potential energy functions have shown to be quite flexible and transferable in characterizing PT reactions in quite diverse chemical systems. The morphing transformation of MMPT force field param- eter, starting from one of our prototype systems to develop a new force field for a new molecular system which exhibits a similar topology in the PES along the proton reac- tion coordinates, has been shown to be successfully applicable in various examples. Energy scaling has been employed to investigate the effect on the proton transfer os- cillation in NH+ 4 · · ·NH3. New parameters through morphing have been developed for protonated diglyme, as well as for double proton transfer in 2PY2HP and for as- partic acid and water as model system for PT reactions in the active site of bacterial ferredoxin I. We applied the MMPT force field to investigate the vibrational infrared spectra of proton-bound species and explored the relationship of infrared spectra for protonated water dimer and protonated diglyme. The results for protonated water dimer compared well with other high-level calculations. Besides the further system- atic development of the morphing approach one can also employ the force field in combination with Feynman path integral methods. The MMPT force field could be a viable alternative to lower level quantum mechanical methods because the accuracy of the force field is only limited by the initial determination of the underlying PES for the PT of interest

Pulmonary Hypertension in Adults with Congenital Heart Disease: Real-World Data from the International COMPERA-CHD Registry

Introduction: Pulmonary hypertension (PH) is a common complication in patients with congenital heart disease (CHD), aggravating the natural, post-operative, or post-interventional course of the underlying anomaly. The various CHDs differ substantially in characteristics, functionality, and clinical outcomes among each other and compared with other diseases with pulmonary hypertension. Objective: To describe current management strategies and outcomes for adults with PH in relation to different types of CHD based on real-world data. Methods and results: COMPERA (Comparative, Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension) is a prospective, international PH registry comprising, at the time of data analysis, >8200 patients with various forms of PH. Here, we analyzed a subgroup of 680 patients with PH due to CHD, who were included between 2007 and 2018 in 49 specialized centers for PH and/or CHD located in 11 European countries. At enrollment, the patients’ median age was 44 years (67% female), and patients had either pre-tricuspid shunts, post-tricuspid shunts, complex CHD, congenital left heart or aortic disease, or miscellaneous other types of CHD. Upon inclusion, targeted therapies for pulmonary arterial hypertension (PAH) included endothelin receptor antagonists, PDE-5 inhibitors, prostacyclin analogues, and soluble guanylate cyclase stimulators. Eighty patients with Eisenmenger syndrome were treatment-naïve. While at inclusion the primary PAH treatment for the cohort was monotherapy (70% of patients), with 30% of the patients on combination therapy, after a median observation time of 45.3 months, the number of patients on combination therapy had increased significantly, to 50%. The use of oral anticoagulants or antiplatelets was dependent on the underlying diagnosis or comorbidities. In the entire COMPERA-CHD cohort, after follow-up and receiving targeted PAH therapy (n = 511), 91 patients died over the course of a 5-year follow up. The 5-year Kaplan–Meier survival estimate for CHD associated PH was significantly better than that for idiopathic PAH (76% vs. 54%; p < 0.001). Within the CHD associated PH group, survival estimates differed particularly depending on the underlying diagnosis and treatment status. Conclusions: In COMPERA-CHD, the overall survival of patients with CHD associated PH was dependent on the underlying diagnosis and treatment status, but was significantly better as than that for idiopathic PAH. Nevertheless, overall survival of patients with PAH due to CHD was still markedly reduced compared with survival of patients with other types of CHD, despite an increasing number of patients on PAH-targeted combination therapy

Search for dark matter produced in association with bottom or top quarks in √s = 13 TeV pp collisions with the ATLAS detector

A search for weakly interacting massive particle dark matter produced in association with bottom or top quarks is presented. Final states containing third-generation quarks and miss- ing transverse momentum are considered. The analysis uses 36.1 fb−1 of proton–proton collision data recorded by the ATLAS experiment at √s = 13 TeV in 2015 and 2016. No significant excess of events above the estimated backgrounds is observed. The results are in- terpreted in the framework of simplified models of spin-0 dark-matter mediators. For colour- neutral spin-0 mediators produced in association with top quarks and decaying into a pair of dark-matter particles, mediator masses below 50 GeV are excluded assuming a dark-matter candidate mass of 1 GeV and unitary couplings. For scalar and pseudoscalar mediators produced in association with bottom quarks, the search sets limits on the production cross- section of 300 times the predicted rate for mediators with masses between 10 and 50 GeV and assuming a dark-matter mass of 1 GeV and unitary coupling. Constraints on colour- charged scalar simplified models are also presented. Assuming a dark-matter particle mass of 35 GeV, mediator particles with mass below 1.1 TeV are excluded for couplings yielding a dark-matter relic density consistent with measurements