Výpočetní studium TiO2-katalyzované syntézy acyclonucleosidů z formamidu: Implikace pro teorii vzniku života

TiO2-katalyzovaná syntéza nukleosid v nevodném prost edí formamidu, probí- hající p es acyklonukleosidové meziprodukty, p edstavuje alternativní cestu pro vznik monomerick˝ch jednotek nukleov˝ch kyselin, která by mohla vy eöit pro- blém spojen˝ s vytvo ením --glykosidické vazby mezi nukleovou bazí a cukern˝m zbytkem. V p edloûené v˝po etní studii je p edstavena moûná reak ní cesta pro prebiotickou, TiO2-katalyzovanou syntézu purinov˝ch C2- a C3-acyklonukleosid v prost edí formamidu, která nevyûaduje fotokatalytick˝ nebo radikálov˝ me- chanizmus. Maximální vypo tená aktiva ní energie podél reak ní koordináty, odpovídající p ibliûn 32 kcal·mol≠1 , je v experimentálních podmínkách Saladi- novy syntézy probíhající p i teplot 160 ¶ C dostupná. Ukazujeme, ûe deprotonace methylenového uhlíku formaldehyd hydrátu, probíhající pravd podobn na defekt- ním povrchu anatasu, p edstavuje rychlost ur ující krok celé reakce. Naöe v˝po ty jsou tak ve shod s p edstavou Saladina a jeho koleg o katalytické funkci TiO2 povrchu p i syntéze purinov˝ch acyklonukleosid v horkém roztoku formamidu.The TiO2-catalyzed synthesis of nucleosides in non-aqueous formamide environ- ment via so-called acyclonucleoside intermediates represents an alternative way for the emergence of nucleic acids monomeric units, which could address the the fundamental problem associated with the formation of a --glycosidic bond between a nucleobase and a sugar moiety. In this computational contribution we present a plausible reaction route for the prebiotic TiO2-catalyzed synthesis of purine C2- and C3-acyclonucleosides in formamide, which does not require photocatalytic or radical chain mechanisms. The maximum computed activation energy along the proposed reaction channel is ≥ 32 kcal·mol≠1 , which is clearly feasible under the experimental conditions of the Saladino synthesis. We show that the rate determining step of the entire reaction path is the deprotonation of the formaldehyde hydrate methylene carbon occurring likely on defective binding sites of an anatase surface. Our calculations thus support the view of Saladino et al. about the catalytic role of the TiO2 surface in the one-pot synthesis of purine acyclonucleosides in heat formamide solution.Department of Chemical Physics and OpticsKatedra chemické fyziky a optikyMatematicko-fyzikální fakultaFaculty of Mathematics and Physic

Deriving predictive pathophysiological markers from ICP analysis

Deriving predictive pathophysiological markers from ICP analysis RNDr. Arnošt Mládek, Ph.D. December 13, 2021 Abstract Intracranial pressure (ICP) is an irreplaceable neurointensive care parameter and is an area under intensive research. The great diagnostic importance of ICP is underlied by two factors: (1) the central nervous system (CNS) is placed in a rigid cranial vault and even small local expansive processes (e.g. tumors, abscesses, bleeding) may lead to intracranial hypertension; (2) a specific property of the CNS is a rather uniform response to various pathological events since many etiologically heterogeneous diffuse injuries of neural tissue lead to oedema elevating ICP. The complexity of ICP monitoring stems from the neurosurgical insertion of the pressure sensor into the intracranial space and the associated risks of bleeding, neuroinfection and brain tissue damage. Intracranial pressure is more than just a number on a bedside monitor, even though in clinical practice this simplification is rather common. Similarly to electrocardiogram (ECG) signals whose information content goes well beyond heart rate calculation, understanding of ICP dynamics can provide us with insight into the current clinical status as well as prediction of further evolution. The mainstay of the dissertation thesis are..

Computational Study of the TiO2-Catalyzed Synthesis of Acyclonucleosides from Formamide: Implications for the Origin of Life

The TiO2-catalyzed synthesis of nucleosides in non-aqueous formamide environ- ment via so-called acyclonucleoside intermediates represents an alternative way for the emergence of nucleic acids monomeric units, which could address the the fundamental problem associated with the formation of a --glycosidic bond between a nucleobase and a sugar moiety. In this computational contribution we present a plausible reaction route for the prebiotic TiO2-catalyzed synthesis of purine C2- and C3-acyclonucleosides in formamide, which does not require photocatalytic or radical chain mechanisms. The maximum computed activation energy along the proposed reaction channel is ≥ 32 kcal·mol≠1 , which is clearly feasible under the experimental conditions of the Saladino synthesis. We show that the rate determining step of the entire reaction path is the deprotonation of the formaldehyde hydrate methylene carbon occurring likely on defective binding sites of an anatase surface. Our calculations thus support the view of Saladino et al. about the catalytic role of the TiO2 surface in the one-pot synthesis of purine acyclonucleosides in heat formamide solution

Deriving predictive pathophysiological markers from ICP analysis

Analýza ICP za účelem stanovení predikčních patofyziologických markerů RNDr. Arnošt Mládek, Ph.D. 13. prosince 2021 Abstrakt Nitrolební tlak (ICP) představuje jeden z nezastupitelných parametrů neurointenzivní péče a jako takový je předmětem intenzivního vědeckého výzkumu. Diagnostický význam ICP je podmíněn dvěma faktory: (1) umístěním centrální nervové soustavy (CNS) v pevné kostěné schránce, kdy lokální expanzivní procesy (nádory, abscesy, krvácení) se, i při relativně malých objemech, mohou projevit nitrolební hypertenzí; (2) specifickou vlastností CNS reagovat relativně uniformně na různé patologické situace, nebot' etiologicky různá difuzní poškození nervové tkáně vedou k rozvoji edému, který je opět příčinou elevace ICP. Komplikací monitorace ICP je nutnost neurochirurgického zavedení tlakového čidla do nitrolebního prostoru, a s tím souvisejících rizik jako krvácení, neuroinfekce a traumatizace tkáně. Nitrolební tlak je více než číslo na monitoru, přestože je na tuto informaci v klinické praxi často redukován. Podobně, jako jde informační obsah EKG vysoko nad rámec výpočtu tepové frekvence, pochopení dynamiky ICP nám může mnohé napovědět nejen o aktuálním stavu, ale i prognóze pacienta....Deriving predictive pathophysiological markers from ICP analysis RNDr. Arnošt Mládek, Ph.D. December 13, 2021 Abstract Intracranial pressure (ICP) is an irreplaceable neurointensive care parameter and is an area under intensive research. The great diagnostic importance of ICP is underlied by two factors: (1) the central nervous system (CNS) is placed in a rigid cranial vault and even small local expansive processes (e.g. tumors, abscesses, bleeding) may lead to intracranial hypertension; (2) a specific property of the CNS is a rather uniform response to various pathological events since many etiologically heterogeneous diffuse injuries of neural tissue lead to oedema elevating ICP. The complexity of ICP monitoring stems from the neurosurgical insertion of the pressure sensor into the intracranial space and the associated risks of bleeding, neuroinfection and brain tissue damage. Intracranial pressure is more than just a number on a bedside monitor, even though in clinical practice this simplification is rather common. Similarly to electrocardiogram (ECG) signals whose information content goes well beyond heart rate calculation, understanding of ICP dynamics can provide us with insight into the current clinical status as well as prediction of further evolution. The mainstay of the dissertation thesis are...Department of Neurosurgery and Neurooncology First Faculty of Medicine Charles University and Military University Hospital PragueNeurochirurgická a neuroonkologická klinika 1. LF UK a ÚVN1. lékařská fakultaFirst Faculty of Medicin

Ion Binding to Quadruplex DNA Stems. Comparison of MM and QM Descriptions Reveals Sizable Polarization Effects Not Included in Contemporary Simulations

Molecular mechanical (MM) force fields are commonly employed for biomolecular simulations. Despite their success, the non-polarizable nature of contemporary additive force fields limits their performance, especially in long simulations and when strong polarization effects are present. Guanine quadruplex D(R)NA molecules have been successfully studied by MM simulations in the past. However, the G-stems are stabilized by a chain of monovalent cations which create sizable polarization effects. Indeed, simulation studies revealed several problems which have been tentatively attributed to the lack of polarization. Here we provide a detailed comparison between quantum-chemical (QM) DFT-D3 and MM Potential Energy Surfaces of ion binding to G-stems and assess differences which may affect MM simulations. We suggest that MM describes binding of a single ion to the G-stem rather well. However, polarization effects become very significant when a second ion is present. We suggest that the MM approximation substantially limits accuracy of description of energy and dynamics of multiple ions inside the G-stems and binding of ions at the stem-loop junctions. The difference between QM and MM descriptions is also explored using symmetry-adapted perturbation theory and Quantum Theory of Atoms in Molecules analyses, which reveal delicate balance of electrostatic and induction effects