Public Defence 15 December 2022

Title: Extending relativistic linear response theory to address solvent effects

Abstract: The central aim of this thesis is to derive, implement and test new methods to calculate various types of spectroscopies of compounds containing heavy elements in an aqueous environment. Methods that can target such systems have to consider the following:
(i) It is crucial to take relativistic effects into account.
(ii) Modeling of larger systems is expensive in quantum chemistry. Thus, cheaper options need to be considered
for the water solvent.
(iii) Methods to calculate electronic spectra have to be able to model electronic excitations properly.
(i) The relativistic effects can be obtained by solving the Dirac equation. This yields a four-component wave function, but methods based on only two-components have been developed in this thesis. (ii) Larger systems can be tackled by dividing them into a region that is treated by methods from electronic structure theory, and a larger environment that is treated classically as a collection of localized static multipole moments (charges, dipole moments, etc.). In most such hybrid schemes (called QM/MM) we only take into account how the static multipole moments in the environment influence the wave function in the QM region. In this thesis, however, we allow mutual polarization of the regions through the polarizable embedding (PE) model. (iii) We calculate excited state properties through linear response theory. This has been developed to work with a variety of approximate state wave functions and has been extended to a relativistic framework. Moreover, it has been combined with PE. Yet, regular linear response theory suffers from problems in non-resonant regions of spectra. For this, we consider a variant of linear response theory, called the complex polarization propagator. Here, the life-times of the excited states are included in the response equations. This allows the calculation of spectra in regions that are problematic in regular response theory.
In this thesis, we have devised a method that combines relativistic CPP within a polarizable embedding framework. We employ the method on light-activated platinum complexes with application in chemotheraphy. Here, both relativistic and solvent effects are crucial to model the excitation processes. Moreover, we also consider the calculation of electronic circular dichroism for chiral organic molecules that contain heavy elements like iodine

Link: https://lup.lub.lu.se/record/3adae5cd-efc4-4f08-8e42-aae2f9cc2072

Public Defence 9 December 2022

Title: Towards a multiconfigurational description of the electronic structure in solids

Abstract: Materials of ionic crystals are ubiquitous in industrial chemistry.
For example, materials such as cerium dioixde (CeO2) are used in both self-cleaning ovens and to clean exhaust fumes from cars.
Other materials, such as titanium dioixde (TiO2) has been used in the solar-cell industry.
So-called garnets are used in several lasers.

In common for all of these areas of application, is that they are dependant on the motion of the electrons in these materials.
In order to understand how electrons behave and interact, quantum mechanics is required.
A major problem that immediately arises when applying quantum mechanics to crystalline materials, is that crystals are, from a quantum mechanical perspective, enormous.
One single crystal can contain as many as Avogradro's number of atoms.
Quantum mechanical calculation are very demanding, with even the most approximate methods available today being limited to around 10 000 atoms.
The type of methods used in this thesis, generally known as wavefunction theory, are roughly limited to around 100 atoms, depending a bit on what part of the periodic table that is explored and what type of property that is studied.

Methods that fall within wavefunction theory have the advantage against more approximate methods that they follow a fairly strict ladder of increasing accuracy.
In other words, the predicted results can, in principle, be improved by choosing methods from higher up on the ladder.
Of course, the higher up on the ladder a method is, the more computationally expensive it is.
It is therefore not necessarily affordable to move enough steps on the ladder, such that the desired accuracy can be reached.
For that reason, there needs to be some form om compromise when modelling crystals -- in order to improve the description of the electronic structure, the atomic structure has to become more approximate.
Models of that kind are usually referred to as embedding methods.

The purpose of this thesis has been to develop an embedding method for crystalline ionic materials.
This was achieved by developing a computer code called SCEPIC, that generates so-called ab-inito model potentials.
As a part of this thesis work, this method was evaluated in order to provide guidance to other researchers on how to best apply this method.

Link: https://lup.lub.lu.se/record/c191b556-0c2e-4c78-86ad-62302abf3359

Public Defence 7 October 2022

Title: Assessing the structural and dynamical properties of concentrated solutions of the disordered proteins Histatin 5 and its tandem repeat

Abstract: Intrinsically disordered proteins are distinguished by a lack of distinct three-dimensional structure, existing instead as an ensemble of heterogenous structures. In this research, the effect of crowding on these proteins is investigated using a combined approach of experiment and computer simulation, mainly using coarse-grained simulation models to make simulation computationally feasible at the high concentration conditions crowding is displayed.
Firstly, the saliva protein Histatin 5 (Hst5) is studied with SAXS, where a selection of coarse-grained models were evaluated using the SAXS data. It was determined that no model could provide adequate simulation-experiment agreement, but a best-performing model could be established. This model predicted moderate change in structure with crowding in the case of Histatin 5.
It was postulated the moderate effect of crowding on Histatin 5 was due to its short sequence-length. Thus, the dimer of Hst5 was formed and subjected to investigation by SAXS and computer simulation for crowding effects. The dimer was more challenging to model with a coarse-grained model, and circular dichroism data suggested secondary structures to be present, which a coarse-grained model cannot capture. Atomistic modelling followed, which however did not perform better than the coarse-grained models, showing the importance of further developing these models to represent intrinsically disordered proteins.
Atomistic modelling was also performed at high concentrations of Hst5 5, combined with quasi-elastic neutron spectroscopy to elucidate diffusion behaviour at crowded conditions. Diffusion decreased with increasing protein concentration, with temperature effects following Stokes-Einstein beha- viour and increses in salt content to decrease diffusion. Depending on assumptions on the relation between effective- and translational-diffusion, the atomistic model displayed semi-quantitative agreement with experiment.
Using neutral polymeric crowders rather than self-crowding showed no impact on structure, as investigated by SAXS. Using DLS did as well not reveal any crowding impact, with the exception of Ficoll®, where Hst5 seemed to modulate Ficoll® self-crowding behaviour in terms of diffusion, decreasing the self-crowding effect. Several coarse-grained models showed similar non-existant effects on structure by crowding, with small deviations from experiment.
Benchmarking three coarse-grained models indicate higher degree of finegraining and additional parameters does necessarily follow the intuitive notion of increasing performance, with the most advanced not having as good performance as the two simpler models in terms of predicting radius of gyration.

Link: https://lup.lub.lu.se/search/publication/1704a974-e825-4c64-a0e9-54fe79d81a14

Public Defence 10 June 2022

Title: Polymer-Mediated Interactions and Phase Behaviour of Polymer-Particle Dispersions

Abstract: Interactions between colloidal particles can be modelled by particles grafted with polymers. In this work, structural and physical properties of colloids are investigated under variation of parameters such as pH, ionic strength, and temperature, where aggregation and cluster formation can be monitored in aqueous solution. Being the subject of our work, in particular, we show that linear or polymer-like clusters can be formed if long-ranged repulsive barriers are combined with very short-ranged attractive minimums stimulating particles to form highly anisotropic structures. This is adjusted by changing the properties of particles and the dispersing medium. Besides, we utilize Metropolis Monte Carlo (MC) simulation to investigate the behavioural change of these particles with a focus on the types of clusters formed. A simplistic potential of mean force is adopted for the simulations, but we also invoke a more elaborate model, to demonstrate that similar interactions can be obtained when the grafted chains are treated explicitly. An important criterion in these studies is that the particle size is large enough to allow structural analyses via microscopy. The range of electrostatic interactions is adjusted by the ionic strength, and the strength of the short-ranged attraction is changed via hydrophobicity regulation of the grafted layer through temperature variation. The results revealed that highly anisotropic structures which resemble linear or branched polymers were the clusters at equilibrium. We could also investigate the effect of polymer addition to the particle dispersions. We could detect a non-monotonic temperature dependent aggregation of particles from attraction to repulsion to attraction, where the polymer-mediated interactions were repulsive. The results were validated against experiments.
The next phase of this work is devoted to the study on capillary induce phase transitions with an experimental focus on polymer solutions containing PNIPAM at the presence of hydrophobic surfaces (mesoporous silica) as a function of pH, temperature and chain length. The capillaries/confined geometries are known to influence the phase diagram of polymer solutions where condensation of bulk solutions may occur close to the surfaces. This work is performed using a combination of experiments and theories where a shift to the LCST (lower critical separation temperature) is presumed to occur, resulting in a capillary-induced decrease in the LCST. 

Link: https://lup.lub.lu.se/record/ff456b77-1b1f-45e8-ba29-1ba15973124b

Public Defence 3 June 2022

Titel: Computational protein crystallography : How to get the most out of your data.

Abstract: It is important to obtain accurate three dimensional structures of molecules and proteins to understand and predict their function and behaviour. X-ray crystallography is the major technique to determine three dimensional structures of proteins. Although there have been major improvements on the experimental side in determining crystallographic data, only small progress has been made on the computational side to get a correct model and
interpretation of this data.
In small-molecule crystallography, some of the shortcomings in the model have already been overcome, but in protein crystallography they still remain. Therefore, we have adapted the Hirshfeld atom refinement from small-molecule crystallography to make it available also to protein crystallography. This enables improved modelling of high-resolution protein data. To achieve this goal, we combined the molecular fractionation with conjugate caps approach with the Hirshfeld atom refinement. We call this combined method fragHAR. With fragHAR, we could perform the first Hirshfeld atom refinement of a metalloprotein.
Furthermore, we improved and applied the quantum refinement method, which employs quantum mechanics calculations to obtain a chemically and physically correct model for all parts of the protein, especially the active site. With quantum refinement, it is possible to distinguish between different interpretations of the structure, e.g. the elemental composition or the protonation state, even from medium-resolution crystallographic data. In this thesis, quantum refinement was improved for highly-charged systems by applying a continuum-solvent description of the surroundings in the quantum mechanics calculation. Furthermore, quantum refinement was applied to settle the nature of the unusual bidentate ligand in V-nitrogenase and the protonation state of the MoFe cluster in Mo-nitrogenase when inhibited by CO. For a recent structure of Mo-nitrogenase, we showed that there is no experimental support for the suggestion that N 2 is bound to the MoFe-cluster and presented a more likely model. We have also identified the most probable protonation states of the active site in acetylcholinesterase before and after inhibition by nerve agents. Finally, for triosephosphate isomerase we used a joint X-ray and neutron quantum refinement to investigate the hydrogen bond between an inhibitor and Lys-13.

Link: https://lup.lub.lu.se/record/f39d3c47-e566-472a-8277-2c565ad64c20

Public Defence 25 May 2022

As a PhD student in theoretical chemistry, i developed theoretical models that describe charged particles close to conducting surfaces. Such systems are common in both biological and non-biological systems. Because of my interest in programming i got the opportunity to develop my own simulation software, which i used to study these systems. One particular system of interest was electrical double layer capacitors (EDLCs). In EDLCs an electrolyte is confined between conducting electrodes. Using the methods we developed we were able to simulate these systems, and study the behaviour of the electrolyte as a constant potential was applied between the electrodes.

The thing that i will remember most of my time here, is not the research. The thing that makes theoretical chemistry great is the people, and in this regard i think it is a unique place. No matter who you are, you will always find a friend at theoretical chemistry.

Public Defence 8 April 2022

The thesis, Modeling of inorganic ions in aqueous solution, focuses on the design and application of atomistic simulation models, or force fields, for inorganic ions.

The lack of a thermodynamically robust force field for the thiocyanate ion motivated the development of a new force field that could reproduce both bulk and interfacial properties for a wide range of salt concentrations. The new, carefully validated force field provides novel insight at the molecular scale into the experimentally observed differences between two thiocyanate salts, NaSCN and KSCN. The force field was further applied in a study of the consecutive binding of potassium ions to a ditopic receptor: a bis-crown ether analogue of Tröger’s base.  While a counterintuitive enthalpic stabilization of the binding of the second potassium was observed experimentally for all studied salts, KCl, KI, KSCN, and K2SO4, the enhanced stabilization observed for KSCN was studied in light of the weaker hydration of the thiocyanate ion compared to the other studied anions, resulting in an enrichment of thiocyanate ions close to the receptor.

A large part of the research was devoted to the development and implementation of methods in the simulation software Faunus, such as the q-potential for handling long-ranged electrostatic interactions, the preferential sampling method for improving sampling, and the charge move method to enable the direct displacement of charges. Combining these with the Wang-Landau algorithm resulted in a platform of methods for efficient calculation of solvation free energies of ions.