1,189 research outputs found
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Geometric Learning for Quantum-Informed, Machine Learning and Analysis of Electrostatic Preorganization
No full textThis thesis is organized in a slightly unconventional fashion: algorithms lead and appli-cations fill out the content. I think this emphasizes my interests during graduate school -
I built algorithms and tools to address issues that were otherwise inaccessible to different
areas of computational chemistry (including applied machine learning) and enzymology. Two
sets of scientific thrusts underscore the bulk of my work: algorithms to analyze dynamic,
heterogeneous fields in the context of enzymology and flexible machine learning algorithms,
including those that leverage quantum descriptors, for rigorous molecular and reaction-level
properties. Each section will include grounding on applications and broader impacts for
the reader as well. Now we pivot to discussing the main thrusts and outlining each chapter
briefly.General ML and Quantum Theory of Atoms-in-Molecules (QTAIM): QTAIMserves as a mathematical decomposition algorithm for electronic basins within a molecule.
The algorithm intakes molecular densities, as computed (typically) by density functional
theory (DFT), and uses the flux of density to partition the scalar field into 3-dimensional
atomic basins of density [14, 16]. These objects are known as atomic basins and represent
the quantum atom within a molecule. By constructing these structures, we compute a rich
set of mathematical descriptors that map to many features including energies, bonding,
and electron delocalization. These features have been correlated, in the past, to activation
energies, reactivity, and overall system energies, but these uses largely relied on human
intervention and small datasets [44, 62, 65, 111, 142, 287]. By developing software centered
around high-throughput QTAIM calculations and machine learning, I was able to bring these
descriptors to larger datasets and a wide host of applications.
In Chapter 2, I discuss an algorithm I implemented to predict Diels-Alder reaction
barriers from QTAIM signatures alone. In this study, we showed that QTAIM features, can be
used to surmise reaction barriers while also using machine learning techniques to understand
what signatures were most informative to our models. Here QTAIM electrostatic potentials
and delocalization indices alone were able to yield great performance on withheld datasets.
In addition, we demonstrated that QTAIM features can allow a machine learning model to
generalize, to an extent, to much larger Diels-Alder reactions. This chapter was adapted from
the following: Machine Learning to Predict Diels–Alder Reaction Barriers from the Reactant
State Electron Density. S. Vargas*, M. Hannefarth, Z. Liu, A.N. Alexandrova. Journal of
Chemical Theory and Computation 2021 17 (10), 6203-6213. 10.1021/acs.jctc.1c00623.
In Chapter 3, I discuss a package developed to perform high-throughput QTAIM
calculations on datasets of molecules and reactions. This package is currently adapted to
work with open-source packages such as ORCA and Multiwfn. These softwares, respectively,
compute DFT densities at a user-specified level of theory and subsequently compute QTAIM
descriptors. The package is built with high-performance compute (HPC) in mind as it
can operate on a single dataset with an arbitrary number of concurrent jobs. Here I also
used the package to compute QTAIM values for a diverse set of important and difficult
datasets and developed graph neural networks to predict molecular and reaction properties
leveraging QTAIM as inputs. This chapter was adapted from the following: This was adapted
from High-throughput quantum theory of atoms in molecules (QTAIM) for geometric deep
learning of molecular and reaction properties Santiago Vargas, Winston Gee, and Anastassia
N. Alexandrova. Digital Discovery 2024 3, 987-998.Advancing Analysis of Electric Fields in Proteins: The later chapters follow ourwork in developing algorithms to ingest, interpret, and predict on electric fields in protein
active sites. This work builds on the notion of electrostatic preorganization, a theory that
posits that protein scaffolds arrange to electrostatically catalyse chemical reactions, and
thereby, destabilizing reactants while suppressing transition state energies [299, 301].
Chapter 4 depicts exhaustive efforts to apply heterogenous electric field analysis to
understanding directed evolution in the context of a protoglobin directed evolution (DE)
trajectory. Previous DE efforts optimized protoglobin to efficiently catalyze carbene transfer
reactions. We show that traditional explanations for increased catalytic activity across the
DE lineage, substrate access and binding, cannot account for the dramatic improvements in
protein activity. By tracking the 3-D electric field and using clustering algorithms, we pinpoint
representative structures for QM/MM calculations and show that changes in the electric field,
along DE, improve carbene transfer reactivity. These findings highlight the role electrostatic
organization, notably its dynamic effect, has on determining protein function and points to
its future importance in designing proteins for relevant chemical processes. This chapter is
adapted from Directed Evolution of Protoglobin Optimizes the Enzyme Electric Field. Shobhit
S. Chaturvedi, Santiago Vargas, Pujan Ajmera, and Anastassia N. Alexandrova. Journal of
the American Chemical Society 2024 146 (24), 16670-16680 DOI: 10.1021/jacs.4c03914.
In Chapter 5, I introduce a machine learning framework designed to predict enzyme
functionality directly from the heterogeneous electric fields applied to protein active sites. We
apply this method to a dataset of Heme-Iron Oxidoreductases. Previous studies here, focused
on simple, point electric fields along the Fe-O bond, are insufficient for reasonable accuracy.
On the otherhand, our 3-D, heterogenous model can accurately predict protein activity
without relying on additional protein-specific information. In addition, feature selection
elucidates what electric field components most inform our models and thus highlight important
components to reactivity and selectivity. Finally, we apply previously-mentioned electric
field clustering algorithms and QM/MM calculations to reveal how dynamic complexities in
protein structures can complicate predictions and thus provides a path forward for improved
models in this space. This chapter is adapted from Machine-learning prediction of protein
function from the portrait of its intramolecular electric field. S. Vargas*, S. Chaturvedi, A.N.
Alexandrova. (Accepted, Journal of the American Chemical Society
Frontispiece: Origin of Extraordinary Stability of Square‐Planar Carbon Atoms in Surface Carbides of Cobalt and Nickel
No full textAlloys In their Communication on page 5312 ff., M. Saeys,. A. N. Alexandrova, et al. present a chemical bonding model to explain the special stability and the reconstruction of surface cobalt and nickel carbides containing square-planar carbon atoms
Photochemistry of DNA fragments via semiclassical nonadiabatic dynamics
No full textForming upon absorption of a UV photon, excited states of DNA are subject to nonadiabatic evolution, via either internal conversion (IC) back to the ground state or mutagenesis. Nonadiabatic processes following the formation of the first singlet excited states, S1, in 10 different small DNA fragments--4 single 4′H-nucleosides, 2 Watson-Crick base pairs, and 4 nucleotide quartets--have been investigated. Simulations were done via the nonadiabatic direct trajectory surface hopping semiclassical dynamics. The electronic wave function was obtained with configuration interaction, based on the semiempirical AM1 and PM3 Hamiltonians with fractional orbital occupation numbers. The evolution of the electronic wave function was governed by the time-dependent Schroedinger equation with a locally diabatic representation, intrinsically stable near surface crossings. The nuclei evolved on adiabatic potential energy surfaces, as prescribed by classical Newtonian dynamics, with sudden hops between potential energy surfaces to account for nonadiabatic transitions. The “fewest switches” surface hopping algorithm coupled the quantum and classical parts of the system. The dynamics simulations revealed several routes of nonadiabatic relaxation in these systems, which were not reported previously, and also recovered known routes of IC
Maize Grain Yield response to n Fertilization, CliMate and HYbrids
No full textabstract MikovA, A., P. AlexAndrovA and i. diMitrov, 2013. Maize grain yield response to n fertilization, climate and hybrids. Bulg. J. Agric. Sci., the relationship between soil-climate conditions, rate of nitrogen application, two maize hybrids and maize grain yield under continuous corn production and irrigation was investigated during 17 years period in eight soil climatic regions in Bulgaria. the experiment was monofactorial with four levels of n fertilization. Maize hybrids from two FAo groups (400 and 700) cultivated under irrigation as a monoculture were used. Statistical analyses were performed in order to describe some relations between maize yield and variables, connected with maize growth. According to the results from AnovA analysis factor "n rate" had the highest effect on the variability of maize yield (72.03 %). The influence of "Hybrid" and "Station" -environmental conditions (soils and climate) was quite low -9.51% and 2.01% respectively. Multiple regression analyses showed that n rate, temperature sum and total water use could be successfuly used as yield predictors
Entoloma argus O. V. Morozova, E. S. Popov, A. V. Alexandrova & Noordeloos 2022, sp. nov.
No full textEntoloma argus O.V. Morozova, E.S. Popov, A.V. Alexandrova & Noordeloos, sp. nov. (Figs. 3, 4) Mycobank: MB 843250 Type:— VIETNAM. Gia Lai Province, K’Bang District, Son Lang Commune, Kon Chu Rang Nature Reserve, N 14.505520°, E 108.541610°, 1050 m a.s.l., on soil in middle-mountain evergreen mixed forest with a predominance of Podocarpaceae (Dacrydium elatum, Dacrycarpus imbricatus), Magnoliaceae, Burseraceae (Canarium), Myrtaceae (Syzygium), 26 May 2016, O.V. Morozova (holotype: LE F-312694 (!), isotype in VRTC (!), ITS sequence GenBank OM987263, LSU sequence GenBank OM996175). Etymology:—Ἄργος (Greek), Argus (Lat.) a character from ancient Greek mythology. Argos was a one hundred-eyed giant who paid a service to the goddess Hera. Zeus killed the giant, but Hera remembered the giant by placing his one hundred eyes on the tail of the peacock. His name is used in various combinations in the generic and species names of butterflies of the Lycaenidae (Cupidinidae) family. The new Entoloma species is named after the butterfly Plebejus argus, due to the similarity of color. Diagnosis:— Entoloma argus is characterized by the delicate greyish blue basidiomata with the distinctly translucently striate pileus covered by small dark blue squamules on a paler greyish blue background with contrasting dark blue centre, and the smooth, polished stipe concolorous with pileus. Microscopically, the sterile lamella edge of cylindrical to narrowly clavate colorless cystidia, and rather small 5–6 angled spores are characteristic. Description:— Basidiomata small to medium-sized, collybioid. Pileus 15‒25 mm diam., hemispherical to convex soon expanding to plano-convex with flat to slightly depressed centre, with deflexed then straight margin, hygrophanous, translucently striate almost up to the centre, greyish blue (21 C –D4–7), covered with dark blue squamules, glabrescent with age and discoloring to greyish beige, with dark blue (21 F 6–8) fibrillose center. Lamellae moderately distant, adnate-emarginate, ventricose, white, becoming pinkish, with entire edge concolorous with faces. Stipe 30–60 × 1–1.5 mm, cylindrical, smooth, polished, greyish blue, concolorous with pileus (21 C –D4–7), with white tomentum at base. Context white, greyish under the surface. Smell indistinct, taste not reported. Basidiospores (8.5–)9.5–10(–11.4) × (6.0–)6.5–7(–7.5) μm, Q = (1.3–)1.45–1.5(–1.6), heterodiametrical, with 5–6 angles in side-view. Basidia 24–34 × 8.5–11.5 μm, 1–2-spored or 4-spored, narrowly clavate to clavate, clampless. Cheilocystidia 33–53 × 7.5–14 μm, cylindrical to narrowly clavate, sometimes septate, not pigmented, forming a sterile lamellae edge. Pileipellis a cutis of cylindrical hyphae 2–7 μm diam with trichodermal bundles of ascending hyphae with cylindrical to narrowly clavate terminal elements (46–86 × 14–20 μm) forming the macroscopic squamules and central disk of pileus. Clamp connections absent. Habitat and distribution:—In small groups in middle-mountain evergreen mixed forests. Known from Vietnam. Additional specimens examined:— VIETNAM. Gia Lai Province, K’Bang District, Son Lang Commune, Kon Chu Rang Nature Reserve, on soil in middle-mountain evergreen mixed forest with a predominance of Podocarpaceae (Dacrydium elatum, Dacrycarpus imbricatus), Magnoliaceae, Burseraceae (Canarium), Myrtaceae (Syzygium), path to the waterfall, N 14.51361°, E 108.54621°, 1007 m a.s.l., 25 May 2016, A. Alexandrova (LE F-315916 (!), ITS sequence GenBank OM 987264); ibid., N 14.505520°, E 108.541610°, 1050 m a.s.l., 28 May 2016, I. Semenyuk and E. Popov (LE F-312695 (!), ITS sequence GenBank OM 987262); ibid., on the river bank, 28 May 2016, O. V. Morozova (LE F-315915 (!), ITS sequence GenBank OM 987265). Notes:— Entoloma argus is distinguished from the macromorphologically similar E. ekaterinae O.V. Morozova, Noordel., K. Nara, Dima & Brandrud, in Crous et al. (2019: 413) from the Russian Far East by the more applanate pileus, different pileipellis structure and shape of the cheilocystidia (cylindrical vs. broadly clavate and subglobose). E. subcaesiellum Noordeloos & O.V. Morozova (2010: 243) also described from the Russian Far East possesses a less squamulose pileus with blue squamules on a greyish beige background and microscopically lacks a distinct trichoderm at pileal center. The European E. phaeodiscum Vila & F. Caballero (2007: 41) differs by the absence of cheilocystidia, less pronounced, fading blue coloration, and geographical distribution.Published as part of Morozova, Olga, Popov, Eugene, Alexandrova, Alina, Pham, Thi Ha Giang & Noordeloos, Machiel Evert, 2022, Four new species of Entoloma (Entolomataceae, Agaricomycetes) subgenera Cyanula and Claudopus from Vietnam and their phylogenetic position, pp. 1-21 in Phytotaxa 549 (1) on pages 8-10, DOI: 10.11646/phytotaxa.549.1.1, http://zenodo.org/record/660526
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Design and Evolution of Metalloenzymes Through Multi-Scale Approaches
No full textNatural metalloenzymes are often the most proficient catalysts in terms of their activity, selectivity, and ability to operate at mild conditions. However, metalloenzymes are occasionally surprising in their choice of catalytic metals, and in their responses to metal substitution. Indeed, from the isolated standpoint of producing the best catalyst, a chemist designing from first principles would likely choose a different metal. Due to competing evolutionary pressures, many natural enzymes may not have evolved to be ideal catalysts and can be improved for the isolated purpose of catalysis in vitro when the competing factors are removed. To improve and, in due course, design metalloenzymes, extensive sampling and proper treatment of the electronic structure of the bound metal(s), is required, while seamlessly merging the required techniques to assess energies and entropies, or their changes, for the entire system. Approaching these challenges with a multi-scale approach, the Alexandrova group has developed an accurate and efficient quantum mechanical/molecular mechanics (QM/MM) hybrid dynamics method to model metalloproteins called quantum mechanics/discrete molecular mechanics (QM/DMD). QM/DMD operates through an iterative scheme between QM and MM machineries. DMD is a flavor of molecular dynamics (MD) that approximates the continuous interaction potentials in classical MD with square-well potentials, course-graining the potentials and overall reducing the number of calculations needed. Due to these discretized potentials, DMD is driven by collision events rather than physical forces as in traditional MM and MD. Therefore, the user saves a tremendous amount of time with DMD by solving ballistic equations of motions rather than Newtonian equations of motions. This fast and efficient hybrid dynamics tools has allowed us to investigate various metal-dependent phenomena in natural metalloenzymes such as: 1) exploring Nature’s curious choices for specific metals using two amide hydrolases that contain different metals as a case study, 2) examining protein conformational responses to substrate binding and metal replacement as showcased by the role of a flexible loop β-lactamase in binding antibiotic substrates and 3) investigating how the species of the metal dictates the reaction mechanism in a pair acireductone dioxygenases (ARD/ARD’). Extending outside the realm of naturally occurring enzymes, our tools have the ability to span across formidable challenges such as metalloenzyme design, where stabilization of a transition state of the catalyzed reaction in the specific binding pocket around the metal needs to be achieved. QM/DMD was used in the redesign of a well-studied Zn2+ peptidase, carboxypeptidase A (CPA), an enzyme involved in the breakdown of proteins, with a slight preference for bulky hydrophobic groups. More specifically, the enzyme and substrate system were modified to create specific-specific binding and subsequent experiments proved the mutant to be catalytically active. Additionally, another tool called Eris-QM/DMD was formulated to better gauge the effect of mutation on protein structure during the design process. Eris is a stand-alone package that evaluates protein stability upon mutagenesis. Coupling the software to QM/DMD gives us the distinct advantage of accounting for the effect of the metal during protein alternations. With this diverse set of tools, our future ambitious goals are to install catalytically potent non-physiological metals into proteins. While nature is limited to operating with bio-available elements, some metals such as Ir, Pd, Sc, and Rh, which have been shown to be excellent catalysts, even surpassing physiological metals. If the catalytic activity of these non-physiological metals can be combined with the superb selectivity and mild operational conditions characteristic of proteins, new proficient enzymes may emerge. Another advantage to enzymatic catalysis, done either in vitro, or in vivo, is that it can be cheaper, “greener”, and more efficient than synthetic catalysis. An early endeavor in this frontier of metalloenzyme design involves installing Pd2+ into an existing protein scaffold, specifically for intramolecular hydroarylation of C-C triple bonds to form coumarins
The phosphatidylserine receptor from <it>Hydra </it>is a nuclear protein with potential Fe(II) dependent oxygenase activity
No full textAbstract Background Apoptotic cell death plays an essential part in embryogenesis, development and maintenance of tissue homeostasis in metazoan animals. The culmination of apoptosis in vivo is the phagocytosis of cellular corpses. One morphological characteristic of cells undergoing apoptosis is loss of plasma membrane phospholipid asymmetry and exposure of phosphatidylserine on the outer leaflet. Surface exposure of phosphatidylserine is recognised by a specific receptor (phosphatidylserine receptor, PSR) and is required for phagocytosis of apoptotic cells by macrophages and fibroblasts. Results We have cloned the PSR receptor from Hydra in order to investigate its function in this early metazoan. Bioinformatic analysis of the Hydra PSR protein structure revealed the presence of three nuclear localisation signals, an AT-hook like DNA binding motif and a putative 2-oxoglutarate (2OG)-and Fe(II)-dependent oxygenase activity. All of these features are conserved from human PSR to Hydra PSR. Expression of GFP tagged Hydra PSR in hydra cells revealed clear nuclear localisation. Deletion of one of the three NLS sequences strongly diminished nuclear localisation of the protein. Membrane localisation was never detected. Conclusions Our results suggest that Hydra PSR is a nuclear 2-oxoglutarate (2OG)-and Fe(II)-dependent oxygenase. This is in contrast with the proposed function of Hydra PSR as a cell surface receptor involved in the recognition of apoptotic cells displaying phosphatidylserine on their surface. The conservation of the protein from Hydra to human infers that our results also apply to PSR from higher animals.</p
Volvariella pulla E. F. Malysheva & A. V. Alexandrova, Phytotaxa
No full textVolvariella pulla E.F. Malysheva & A.V. Alexandrova, Phytotaxa 408 (4): 247 (2019) (Figures 4 & 5) MycoBank MB 831060, Faces of Fungi 08024 Description:— Basidiome large. Pileus 70 mm diam., plano-convex with a low broad umbo, brownish grey (6E2) with slightly darker color at the center, dull, dry, non-hygrophanous, with fibrillose to appressed-squamulose surface; margin decurved to straight, crenulate; context light yellow (4A5), soft. Lamellae free, ventricose, close, moderately thin, soft, pale orange (6A3) to brownish orange (6C8) and turning light brown (6D8) with age; edge finely fimbriate, concolorous with faces; lamellulae present, very variable in length, mostly in one tier. Stipe 65 × 4 mm, central, terete, tapered from the base to apex, solid, dark brown (6F4–5), slightly paler near the base, entirely pubescent; context light yellow (4A5); annulus absent. Volva rather thick, mostly free, saccate, fragile, greyish brown (6D3). Spore print pinkish (7A2). Odor indistinct. Taste mild. Basidiospores [60,1,1] (5.5)6–7–7.5(8.0) × 4–4.4–4.5(5) µm (Q = 1.2–1.8, Q* = 1.5), broadly ellipsoid to ellipsoid, oblong, ovoid, thickened wall, hyaline in 5% KOH. Basidia [30,1,1] (16)17–18.1–19(19.5) × (7)7.5–8– 8.5(9) µm (Q = 1.8–2.8, Q* = 2.3), tetrasporic, narrowly to broadly clavate, hyaline in 5% KOH. Cheilocystidia [20,1,1] (24)29–37.5–56(87) × (9)11–12.1–13(17) µm (Q = 1.6–6.4, Q* = 2.8), abundant, varied in size and shape, narrowly to broadly utriform, broadly lageniform, broadly fusiform, lecythiform, thin-walled, hyaline and colorless in 5% KOH. Pleurocystidia [20,1,1] (25)29–36.5–44(56) × (6)12–16.6–19(32) µm (Q = 1.5–4, Q* = 2.2), ellipsoid, obpyriform, utriform, broadly fusiform, lageniform, mostly thin-walled, hyaline in 5% KOH. Hymenophoral trama inverse, made up of thin-walled hyaline hyphae. Pileipellis a trichoderm; terminal elements with light brown (6D5) intracellular pigment, slightly darker on the swollen ends, [20,1,1] 77–177 × 11–31 µm. Stipitipellis a cutis; terminal elements with light brown (6D8) intracellular pigment [20,1,1] 75–162 × 8–15 µm, forming hairs. Clamp connections not seen in any part. Habitat and distribution:—Solitary, on the soil among grasses partly covered with litter. First described from Gia Lai Province in Vietnam. Now it is also known from northern Thailand. Specimen examined:— THAILAND. Chiang Rai Province: Mae Fah Luang University, 20.0449° N, 99.8943° E, lawn, 27 September 2018, P. Sysouphanthong, MFLU 19-1534 (GenBank MT 074696 - ITS). Notes:—According to the protologue, Volvariella pulla has medium to large basidiomes, with greyish brown or ash brown pileus and colored volva; the stipe is beige, ochraceous or greyish brown at base (Malysheva et al. 2019). The specimen from Thailand is morphologically similar to the holotype. However, the stipe was darker (dark brown). This difference might be due to the more advanced maturity or drier condition of the specimen, which was photographed and described after getting back to the laboratory (Figure 4). Volvariella pulla is recorded for the first time from Thailand after it was described from Vietnam in 2019 (Malysheva et al. 2019). Although V. pulla is morphologically most similar to V. rostricystidiata and V. volvacea, it is phylogenetically most closely related to V. guttulosa E.F. Malysheva & A.V. Alexandrova (2019: 242) and V. niveosulcata E.F. Malysheva & A.V. Alexandrova (2019: 240) (Figure 1).Published as part of Niego, Allen Grace T., Sysouphanthong, Phongeun, Thongklang, Naritsada, Hyde, Kevin D., Phonemany, Monthien, Phookamsak, Rungtiwa & Raspé, Olivier, 2021, A new species of Volvariella and the first record of Volvariella pulla (Agaricales: incertae sedis) from Thailand, pp. 237-250 in Phytotaxa 480 (3) on pages 244-246, DOI: 10.11646/phytotaxa.480.3.3, http://zenodo.org/record/541688
Prediction of Two-Dimensional Phase of Boron with Anisotropic Electric Conductivity
No full textTwo-dimensional (2D) phases of boron are rare and unique. Here we report a new 2D all-boron phase (named the it phase) that can be grown on a W(110) surface. The pi phase, composed of four-membered rings and six-membered rings filled with an additional B atom, is predicted to be the most stable on this support. It is characterized by an outstanding stability upon exfoliation off of the W surface, and unusual electronic properties. The chemical bonding analysis reveals the metallic nature of this material, which can be attributed to the multicentered pi-bonds. Importantly, the calculated conductivity tensor is anisotropic, showing larger conductivity in the direction of the sheet that is in-line with the conjugated pi-bonds, and diminished in the direction where the pi-subsystems are connected by single sigma-bonds. The pi-phase can be viewed as an ultrastable web of aligned conducting boron wires, possibly of interest to applications in electronic devices.CSST Scholarship; Postdoctoral Fellowship of the Basque Country [POS 2015 1 0008]; NSF-CAREER [CHE1351968]; Department of Defense; UCLA-IDRE clusterSCI(E)ARTICLE61224-1228
Sirma Alexandrova, Typology and chronology of the hand‐made pottery of the Roman and Early Byzantine period (1st – 6th c.) on the territory of Bulgaria (Dissertations, volume 7), 2013
No full textPanaite Adriana. Sirma Alexandrova, Typology and chronology of the hand‐made pottery of the Roman and Early Byzantine period (1st – 6th c.) on the territory of Bulgaria (Dissertations, volume 7), 2013. In: Materiale şi cercetãri arheologice (Serie nouã), N°12 2016. pp. 287-288
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