Computer simulations explain mutation-induced effects on the DNA editing by adenine base editors.

Adenine base editors, which were developed by engineering a transfer RNA adenosine deaminase enzyme (TadA) into a DNA editing enzyme (TadA*), enable precise modification of A:T to G⋮C base pairs. Here, we use molecular dynamics simulations to uncover the structural and functional roles played by the initial mutations in the onset of the DNA editing activity by TadA*. Atomistic insights reveal that early mutations lead to intricate conformational changes in the structure of TadA*. In particular, the first mutation, Asp108Asn, induces an enhancement in the binding affinity of TadA to DNA. In silico and in vivo reversion analyses verify the importance of this single mutation in imparting functional promiscuity to TadA* and demonstrate that TadA* performs DNA base editing as a monomer rather than a dimer

Molecular electrostatic potentials by systematic molecular fragmentation

A simple method is presented for estimating the molecular electrostatic potential in and around molecules using systematic molecular fragmentation. This approach estimates the potential directly from the electron density. The accuracy of the method is established for a set of organic molecules and ions. The utility of the approach is demonstrated by estimating the binding energy of a water molecule in an internal cavity in the protein ubiquitin

How Water's Properties Are Encoded in Its Molecular Structure and Energies.

How are water's material properties encoded within the structure of the water molecule? This is pertinent to understanding Earth's living systems, its materials, its geochemistry and geophysics, and a broad spectrum of its industrial chemistry. Water has distinctive liquid and solid properties: It is highly cohesive. It has volumetric anomalies-water's solid (ice) floats on its liquid; pressure can melt the solid rather than freezing the liquid; heating can shrink the liquid. It has more solid phases than other materials. Its supercooled liquid has divergent thermodynamic response functions. Its glassy state is neither fragile nor strong. Its component ions-hydroxide and protons-diffuse much faster than other ions. Aqueous solvation of ions or oils entails large entropies and heat capacities. We review how these properties are encoded within water's molecular structure and energies, as understood from theories, simulations, and experiments. Like simpler liquids, water molecules are nearly spherical and interact with each other through van der Waals forces. Unlike simpler liquids, water's orientation-dependent hydrogen bonding leads to open tetrahedral cage-like structuring that contributes to its remarkable volumetric and thermal properties

Ligand-Receptor Interactions

The formation and dissociation of specific noncovalent interactions between a variety of macromolecules play a crucial role in the function of biological systems. During the last few years, three main lines of research led to a dramatic improvement of our understanding of these important phenomena. First, combination of genetic engineering and X ray cristallography made available a simultaneous knowledg of the precise structure and affinity of series or related ligand-receptor systems differing by a few well-defined atoms. Second, improvement of computer power and simulation techniques allowed extended exploration of the interaction of realistic macromolecules. Third, simultaneous development of a variety of techniques based on atomic force microscopy, hydrodynamic flow, biomembrane probes, optical tweezers, magnetic fields or flexible transducers yielded direct experimental information of the behavior of single ligand receptor bonds. At the same time, investigation of well defined cellular models raised the interest of biologists to the kinetic and mechanical properties of cell membrane receptors. The aim of this review is to give a description of these advances that benefitted from a largely multidisciplinar approach

Computational Modeling Methods for Understanding the Interaction of Lignin and Its Derivatives with Oxidoreductases as Biocatalysts

This chapter will be presented as follow. First, a brief introduction to structure and characterization of lignin and its derivatives is presented, as well as their importance as chemical scaffolds for obtaining value-added products in chemical, food, pharmaceutical and agriculture industry. Second, an extensive review of different reports using computational modeling methods—like molecular dynamics simulations, quantum mechanics and hybrid calculation methods, among others—in the understanding of enzyme-substrate interaction and biocatalysis will be presented. Third, and as last part of chapter, some hand picked examples from literature will be chosen as successful cases where the interplay between experiment and computation has given as a result protein engineered oxidoreductases with improved catalytic capabilities

Anioonretseptorite arvutuslik disain ning peremees-külaline seondumise uurimine

Väitekirja elektrooniline versioon ei sisalda publikatsiooneAnioon-retseptor keemia – sobivate retseptormolekulide kasutamine huvipakkuvate anioonide sisalduse või olemasolu määramiseks uuritavast keskkonnast – on kiiresti kasvav uurimisvaldkond. Uute molekulide süntees ning eksperimentaalne uurimine on ajamahukas tegevus ja oleks kasulik, kui retseptorite omadusi oleks võimalik enne nende olemasolu ette ennustada. See, kas ja kui hästi mingi retseptor suudab teise osakese enda külge siduda (retseptor-anioon seondumistugevus), sõltub mitmest faktorist. Arvutuskeemia abil on võimalik uurida osakeste struktuuri lahuses ning hinnata geomeetrilist osakeste kokkusobivust ja seondumise efektiivsust. Doktoritöös uuriti COSMO-RS arvutusliku meetodi rakendamisvõimalusi retseptor-anioon seondumise uurimiseks. Töö tulemusena leiti, et arvutuslikult hinnatud retseptorite seondumistugevus on märgatavalt ülehinnatud, aga meetodi abil on võimalik hinnata retseptorite kasutatavust ning vaadelda retseptor-anioon seondumise geomeetrilisi aspekte. Retseptorite uurimisel on oluline osa ka eksperimentidel. Mikrokalorimeetriga läbi viidud isotermiline kalorimeetriline tiitrimine (reaktsiooni soojusefektide uurimine konstantsel temperatuuril tehtud tiitrimiseksperimendi kaudu) on meetodina laialdaselt kasutatud kõrge seondumistugevusega reaktsioonide uurimiseks. Selleks, et rakendada meetodit anioon-retseptor seondumise uurimiseks, mis tüüpiliselt on võrdlemisi madala seondumistugevusega, oleks vajalik meetodi kasutatavuse uurimine tema rakendusala piiri lähedal ning eksperimendi planeerimise ja läbiviimise tingimuste optimeerimine ning saadud tulemuste mõõtmistäpsuse (mõõtemääramatuse) hinnangu leidmine. Töö tulemusena leiti, et uuritud mikrokalorimeetria eksperimente saab kasutada nõrgalt seonduvate süsteemide reaktsiooniparameetrite hindamiseks ning eksperimentaalselt leitud reaktsioonientalpia hinnangu liitstandardmääramatus jääb vahemikku 1-2 kJ/mol.Anion-receptor chemistry – using suitable receptor molecules to determine the existence or quantity of specific anions from solution environment- is a rapidly developing field of research. As the synthesis and experimental characterization of new receptor molecules is a time-consuming task, it would be useful to be able to predict the characteristics of a new molecule prior to synthesis. The efficiency (binding affinity) of receptor and anion binding depends on multiple simultaneous intramolecular interactions. Computational chemistry allows to study the structure of the chemical species in a solvent environment and estimate the spatial compatibility of the host and guest and the efficiency of binding. The doctoral study investigated the applicability of the COSMO-RS method for studying and characterization of receptor molecule and anion binding. The study found that while computational predictions for absolute values of binding affinities are overestimated by COSMO-RS, the method allows to study the usability of receptor molecules and to investigate geometric aspects of binding. In the study of receptor molecules, experimental characterization of binding is also important. Applications of microcalorimetry for isothermal titration calorimetry (ITC) experiments are commonly used for studying systems with a high binding affinity. Before the method can be applied to study anion-receptor binding – systems that typically exhibit quite low binding affinities – the method should be validated for use near the instrumental limits of application, and the measurement uncertainty should be estimated. The study determined that low volume microcalorimetry can be used to study systems of low binding affinity and the reaction enthalpy can be experimentally determined with a combined standard measurement uncertainty in the range of 1-2 kJ/mol.https://www.ester.ee/record=b542424