Přesné kvantově mechanické výpočty nekovalentních interakcí: Racionalizace rentgenových krystalových geometrií aparátem kvantové chemie

Spolehlivá a jednoduše aplikovatelná pravidla jsou potřebná v oblasti biochemie, supramolekulární chemie i materiálových vědách. Zároveň množství informací, které můžeme získat z rentgenových krystalových struktur o povaze rozpoznávacích procesů, je omezené. Lepší pochopení nekovalentních interakcí, které hrají nejdůležitější roli, je potřebné pro přezkoumání univerzálních pravidel, řídících jakékoliv rozpoznávací procesy. V této práci je prezentován systematický vývoj a studium přesnosti výpočetních metod, doplněný aplikacemi na systémech bílkovina DNA a hostitel host. Ne-empirické kvantově mechanické nástroje (metody DFT-D, MP2.5, CCSD(T) atd.) byly využity v několika projektech. Našli a potvrdili jsme existenci unikátních nízko ležících interakčních energií, vzdálených od zbývajících distribucí v několika párech aminokyselina−báze, které otevírají cestu k univerzálním pravidlům řídícím selektivní navázání jakékoliv sekvence DNA. Dále byly v několika případech provedeny predikce a ověřeny změny Gibbsovy energie (ΔG) a jejich komponentů a nakonec byly pečlivě porovnány s experimenty. Stanovili jsme, že molekula cholinu (Ch+) je vázána o 2.8 kcal/mol silněji (vypočtením ΔG) než acetylcholin (ACh+) v samo-uspořádané tří helikální rigidní kleci, odpovídající K(Ch+)/K(ACh+) = 109, což je v poměrně...There is a need for reliable rules of thumb for various applications in the area of biochemistry, supramolecular chemistry and material sciences. Simultaneously, the amount of information, which we can gather from X-ray crystal geometries about the nature of recognition processes, is limited. Deeper insight into the noncovalent interactions playing the most important role is needed in order to revise these universal rules governing any recognition process. In this thesis, systematic development and study of the accuracy of the computational chemistry methods followed by their applications in protein DNA and host guest systems, are presented. The non-empirical quantum mechanical tools (DFT-D, MP2.5, CCSD(T) etc. methods) were utilized in several projects. We found and confirmed unique low lying interaction energies distinct from the rest of the distributions in several amino acid−base pairs opening a way toward universal rules governing the selective binding of any DNA sequence. Further, the predictions and examination of changes of Gibbs energies (ΔG) and its subcomponents have been made in several cases and carefully compared with experiments. We determined that the choline (Ch+) guest is bound 2.8 kcal/mol stronger (calculated ΔG) than acetylcholine (ACh+) to self-assembled triple helicate rigid...Katedra fyzikální a makromol. chemieDepartment of Physical and Macromolecular ChemistryPřírodovědecká fakultaFaculty of Scienc

From small to big: understanding noncovalent interactions in chemical systems from quantum mechanical models

Noncovalent interactions in complex chemical systems are examined by considering model systems which capture the essential physics of the interactions and applying correlated electronic structure techniques to these systems. Noncovalent interactions are critical to understanding a host of energetic and structural properties in complex chemical systems, from base pair stacking in DNA to protein folding in organic solids. Complex chemical and biophysical systems, such as enzymes and proteins, are too large to be studied using computational techniques rigorous enough to capture the subtleties of noncovalent interactions. Thus, the larger chemical system must be truncated to a smaller model system to which rigorous methods can be applied in order to capture the essential physics of the interaction. Computational methodologies which can account for high levels of electron correlation, such as second-order perturbation theory and coupled-cluster theory, must be used. These computational techniques will be used to study several types (pi stacking, S/pi, and C-H/pi) of noncovalent interactions in two chemical contexts: biophysical systems and organic solids.Ph.D.Committee Chair: Sherrill, C. David; Committee Member: Bredas, Jean-Luc; Committee Member: El-Sayed, Mostafa A.; Committee Member: Harvey, Stephen C; Committee Member: Hernandez, Rigobert

Nekovalentní interakce v plynné fázi a vodném roztoku: Teoretické studium

EAPUr rr|lclltal \ alLlť5' 5 Conclusions :, , . In the ia) part of present work we c intera cti on b etween u d"',il ". . . thy;';; il:'::: :íJTj.:lÍ' lI jl.#.ffiJ,lil itt8:"é'siia small number or*u.",7nJ organió solvent ňr"."i", (CH3.H, solvents yů[T"i^f.completely different interactions between the bases and the b"''" p.'"{ ;' "idilnn il#} il-t ÍT:!fl,-. i: : " o:] Y" .'h:.-S,t.* tu,", ot tt," moleóule Iuórc 'u'r' u property, and the'. .'l,'..,ťff,.'*lt'Lť':.lill:ilF.S'T!,l;situated above or belolthe !Á; ;;i. ;';;lě'"o ri," olašó ň"l"-.\,," ,, unique y"J::fiffii:x::. ."n'o*ison with otr,!. .otu"nt,, uň.'r,"í'ř;;.". are the In the ib) part_of present work based on the MD, SCC_DDFTB_D and ;"",'.Y|Tť'.#1.:."ffi i"T."lrJ'".r""u.'".XincorporateJ."-oŇTduplexwe i) Replacing nucleic acid base by modified nucleobase X leads.*:'] ,o Structural changes of the centrď -uuš"-pui. Gtu.tarrangement of central modified base pairs). ónli with ttresma'lest modified nucleobase p 'r'" Á.iJ.;;*;;.í' (A-P, P-T) stay planar. In the case 'of.B-T, Á-il.;';6 in specificorientation, one of the modified nuú"JÁ""x"*íto.""a outfrom DNA duplex. ii) Incre, .,""olr'iT"i1iTi1fi" or modified nucleobase X increases rhe iii) The highest s.ďectivity among- all base ana|ogue studied wasfound for modified nu"l"obus" O In the secono pu* of...5 Zál,ěr \/ části ia) prezentované práce jsme porovnali stabilitu a molekulovou interakci mezi adeninem...tyminem, guaninem...cýosinem a jejímimetylovanými 11alogy s malým počtem molekul vody a organických rožpouŠtědel.(CH3óH, DMSO a CHCI3). Pozorovali jsme odlišnéinterakce mezibázemi a studovanými solventy. Zatimco voda a CH3OH stabilizují S struktury párit bazi vetšímpočtem vodíkových vazeb než je moŽno v HB strukturacň, čHct:molekula nemá tuto v|astnost a jsou preferovány HB struktury s molekulami rozpouštědla nad a pod rovinou bází. DMSo molekula je jedinečná svou velikostí ve srovnání s ostatními rozpouštědly a mezi páry bazí s DMSo rozpouštědlem jsou nejvíce zastoupené jsou T struktury. . V části ib) prezentované práce jsme dospěli k několika závěrum za|oženýmna MD, SCC-DFTB-D a CoSMo výpočtech: i) nahrazení nukleové báze modifikovanou nukleobází X vede převážně ke strukturálním změnám centrálního páru (patrové uspořádání centrálního modifikovaného páru). Pouze s nejmenšími modifikovanými nukleobázemi P' centrá,lni pár bazí (A-P' P-T a P-P) zustane planární. V případě B-T' A-B nebo D- D ve specifické orientaci je jedna z modifikovaných bazi X výIačenaven z DNA duplexu. ii) Se stoupajícíaromaticitou modifikovaných nukleobazí X roste stabilita patrového uspořádání iii) Nejvyššíselektivita mezi všemi...Department of Physical and Macromolecular ChemistryKatedra fyzikální a makromol. chemieFaculty of SciencePřírodovědecká fakult

Determination of Noncovalent Intermolecular Interaction Energy from Electron Densities

Noncovalent intermolecular interactions, widely found in molecular clusters and bio-molecules, play a key role in many important processes, such as phase changes, folding of proteins and molecular recognition. However, accurate calculation of interaction energies is a very difficult task because the interactions are normally very weak. Rigorous expressions for the electrostatic and polarization interaction energies between two molecules A and B, in term of the electronic densities, have been programmed: (see formula in document). Z is atomic charge, ρ0 is the electron density of the isolated molecule and Δρind is the electron density change of the molecule caused by polarization. With some approximations, procedures for electrostatic and polarization energy calculations were developed that involve numerical integration. Electrostatic and polarization energies for several bimolecular systems, some of which are hydrogen bonded, were calculated and the results were compared to other theoretical and experimental data. A second method for the computing of intermolecular interaction energies has also been developed. It involves a “supermolecule” calculation for the entire system, followed by a partitioning of the overall electric density into the two interacting components and then application of eq. (1) to find the interaction energy. In this approach, according to Feynman’s explanation to intermolecular interactions, all contributions are treated in a unified manner. The advantages of this method are that it avoids treating the supersystem and subsystems separately and no basis set superposition error (BSSE) correction is needed. Interaction energies for several hydrogen-bonded systems are calculated by this method. Compared with the result from experiment and high level ab initio calculation, the results are quite reliable

Atom-centered potentials for describing London dispersion forces in density functional theory

The Kohn-Sham formulation of density functional theory (DFT) has posed itself as one of the most popular and versatile methods for condensed phase studies owing to its reasonable accuracy and affordable computational cost. DFT, in principle, yields exact ground state energy, including dispersion forces that are of primordial importance in chemical and biological systems. Yet with many exchange-correlation functionals in practical use such as the local density approximation or generalized gradient approximations, DFT either provides sporadic results or fails completely to account for these forces. In consequence, various methods offering remedy for this shortcoming have been proposed in this active field of research. In particular, dispersion-corrected atom-centered potentials (DCACPs) serve as a robust and efficient way to include these weak forces in a fully self-consistent manner within current DFT frameworks. The aim of this thesis is twofold: first, to improve the predictive power and the understanding of the DCACP concept; second, applying DCACPs to systems of increasing complexity starting with dimers, continuing through larger clusters and ending with the condensed phase. The success of the second aim not only justifies the use of DCACPs but more importantly, provides insights to the role dispersion forces play in the systems investigated. We first draw on the atoms-in-molecules theory and a multi-center density expansion to justify the form and universality of DCACPs. A library of DCACPs calibrated with an improved penalty functional against high-level ab initio references is presented. With the library in hand, we extend our studies to systems of biological significance, mainly constituents of proteins and DNA; polycyclic aromatic molecules intercalated in between segments of DNA are the center of focus. The application of DCACPs is then furthered to the condensed phase and the importance of van der Waals interactions in liquid water is investigated

Computational strategies for the accurate thermochemistry and kinetics of gas-phase reactions

This PhD thesis focuses on the theoretical and computational modeling of gas phase chemical reactions, with a particular emphasis on astrophysical and atmospherical ones. The ability to accurately determine the rate coefficients of key elementary reactions is deeply connected to the accurate determination of geometrical parameters, vibrational frequencies and, even more importantly, electronic energies and zeropoint energy corrections of reactants, transition states, intermediates and products involved in the chemical reaction, together with a suitable choice of the statistical approach for the rate computation (i.e. the proper transition state theory model). The main factor limiting the accuracy of this process is the computational time requested to reach meaningful results (i.e. reaching subchemical accuracy below 1 kJ mol−1), which increases dramatically with the the size of the system under investigation. For small-sized systems, several nonempirical procedures have been developed and presented in the literature. However, for larger systems the well-known model chemistries are far from being parameter-free since they include some empirical parameters and employ geometries which are not fully reliable for transition states and noncovalent complexes possibly ruling the entrance channels. Based on these premises, this dissertation has been focused on the development of new “cheap” composite schemes, entirely based on the frozen core coupled cluster ansatz including single, double, and (perturbative) triple excitation calculations in conjunction with a triple-zeta quality basis set, including the contributions due to the extrapolation to the complete basis set limit and core-valence effects using second-order Møller- Plesset perturbation theory. For the first time the “cheap” scheme has been extended to explicitly-correlated methods, which have an improved performance with respect to their conventional counterparts. Benchmarks with different sets of state of the art energy barriers, interaction energies and geometrical parameters spanning a wide range of values show that, in the absence of strong multireference contributions, the proposed models outperforms the most well-known model chemistries, reaching a subchemical accuracy without any empirical parameter and with affordable computer times. Besides the composite schemes development efforts, a robust protocol for disclosing the thermochemistry and kinetics of reactions of atmospheric and astrophysical interest, rooted in the so-called ab initio-transition-state-theory-based master equation approach have been thoroughly investigated and validated

Interakce mezi vedlejšími řetězci aminokyselin v proteinech

Charles University in Prague Faculty of Science Department of Physical and Macromolecular Chemistry Side-chain Side-chain Interactions in Proteins Doctoral Thesis Abstract RNDr. Karel Berka Supervisors: Prof. Ing. Pavel Hobza, DrSc., FRSC RNDr. Jiří Vondrášek, CSc. Institute of Organic Chemistry and Biochemistry AS CR Center for Biomolecules and Complex Molecular Systems Praha 2009 2 Introduction Proteins are the most versatile and useful molecules in the cellular arsenal. They are the best catalysts the nature knows. Proteins cover the biggest amount of the cellular functions with range from metabolism and signaling through cell architecture to DNA replication. Variations of their structure and functions are amazing. And yet, they are built from simple building blocks - amino acids. Each amino acid has many possibilities of interactions with its neighborhood and the sequential context manifested through these possibilities is the main reason for the structure variability. The experimental investigation of the character and relative strength of interactions between amino acid residues is difficult. On the other hand, theoretical chemistry methods and techniques of are well suited for such task. They can provide useful information about structure, stability and nature of these interactions. The aim of the...Universita Karlova v Praze Přírodovědecká fakulta Katedra fyzikální a makromolekulární chemie Interakce mezi vedlejšími řetězci aminokyselin v proteinech Souhrn disertační práce RNDr. Karel Berka Školitelé: Prof. Ing. Pavel Hobza, DrSc., FRSC RNDr. Jiří Vondrášek, CSc. Ústav organické chemie a biochemie AV ČR Centrum biomolekul a komplexních molekulárních systémů Praha 2009 7 Úvod Proteiny jsou univerzální a nejpoužívanější buněčné nástroje. Ve schopnosti katalyzovat chemické reakce se jim v přírodě nic nevyrovná. Mají významnou funkci v metabolismu, v buněčné signalizaci, podílí se na procesu ukládání genetické informace a tvoří i mechanickou oporu buňky. Ohromné množství funkcí proteinů s sebou nese i ohromné množství jejich tvarů a struktur. Přesto je každý protein sestaven z jednoduchých stavebních prvků - aminokyselin. Každá z nich má mnoho možností, jak interagovat se svými sousedy. Proměnlivost struktury proteinů pak jedině závisí na sekvenci řazení aminokyselin. Charakter a relativní síla jednotlivých interakcí mezi aminokyselinami se experimentálně stanovuje obtížně, protože je těchto interakcí v každém proteinu příliš mnoho. Na druhou stranu jsou metody teoretické chemie na takovýto úkol dobře přizpůsobeny a mohou vnést alespoň trochu světla do informací o struktuře, stabilitě a původu těchto...Department of Physical and Macromolecular ChemistryKatedra fyzikální a makromol. chemieFaculty of SciencePřírodovědecká fakult