Atomistic modeling and simulation methods facilitate biomedical research from many respects, including structure-based drug design. The ability of these methods to address biologically relevant problems is largely determined by the accuracy of the treatment of complex solvation effects in target biomolecules surrounded by water. The implicit solvent model – which treats solvent as a continuum with the dielectric and non-polar properties of water – offers a good balance between accuracy and speed. Simple and efficient, generalized Born (GB) model has become a widely used implicit solvent responsible for the estimation of key electrostatic interactions. The main goal of this research is to improve the accuracy of protein-ligand binding calculations in the implicit solvent framework. To address the problem (1) GBNSR6, an accurate yet efficient flavor of GB, has been thoroughly explored in the context of protein-ligand binding, (2) a global multidimensional optimization pipeline is developed to find the optimal dielectric boundary made of atomic and water probe radii specifically for protein-ligand binding calculations using GBNSR6. The pipeline includes (3) two novel post-processing steps for optimum robustness analysis and optimization landscape visualization. In the final step of this research, (4) accuracy gain the optimal dielectric boundary can bring in practice is explored on binding benchmarks, including the SARS-CoV-2 spike receptor-binding domain and the human ACE2 receptor. / Doctor of Philosophy / Drug discovery is one of the most challenging tasks in biological sciences as it takes about 10-15 years and $1.5-2 billion on average to discover a new drug. Therefore, efforts to speed up this process or lower its costs are highly valuable. Computer-aided drug design (CADD) plays a crucial role in the early stage of drug discovery. In CADD, computational approaches are used in order to discover, develop, and analyze drugs and similar biologically active molecules, such as proteins. Proteins are an important class of biological macromolecules that perform their functionality mainly through interactions with other molecules, for example, binding to small molecules so-called ligands. Thorough understanding of protein-ligand interactions is central to comprehending biology at the molecular level. In this study, we introduce and analyze a computational model used for protein-ligand binding free energy calculations. A global multidimensional optimization pipeline is developed to find the optimal parameters of the model,˘aparticularly˘athose parameters involved in the dielectric boundary. In order to examine the robustness of the optimal model to unavoidable perturbations and uncertainties, virtually inevitable in any complex system being optimized, a novel robustness metric is introduced. Finally, the robust optimal model is tested on protein-ligand benchmarks, including a complex related to the novel coronavirus. Results demonstrate relatively higher accuracy in terms of binding free energy calculations compared to reference models.

A central goal of computational biophysics and biochemistry is to understand the behavior, interactions, and reactions of molecules, and to interpret and facilitate experimental design. The objective of this thesis research is to use the molecular modeling and simulation techniques to advance our understanding of principles in molecular structure properties, recognition and interaction at the atomic level. First, a physical molecular mechanics model is built to study the conformational properties of depsipeptide, which shows potential for engineered protein mimetics with controllable structure and function. We explore the possible kinase-substrate binding modes and the likelihood of an [alpha]-helix docking interaction within a kinase active site. Finally, efficient physical models based on a polarizable potential function are developed to describe the structural properties and calculate protein-ligand binding affinities accurately for both trypsin and matrix metalloproteinase. / text

Proteins and DNA are large, complex molecules that carry out biological functions essential to all life. Their successful operation relies on adopting specific structures, stabilized by intra-molecular interactions between atoms. The spatial and temporal resolution required to study the mechanics of these molecules in full detail can only be obtained using computer simulations of molecular models. In a molecular dynamics simulation, a trajectory of the system is generated, which allows mapping out the states and dynamics of the molecule. However, the time and length scales characteristic of biological events are many orders of magnitude larger than the resolution needed to accurately describe the microscopic processes of the atoms. To overcome this problem, sampling methods have been developed that enhance the occurrence of rare but important events, which improves the statistics of simulation data. This thesis summarizes my work on developing the AWH method, an algorithm that adaptively optimizes sampling toward a target function and simultaneously finds and assigns probabilities to states of the simulated system. I have adapted AWH for use in molecular dynamics simulations. In doing so, I investigated the convergence of the method as a function of its input parameters and improved the robustness of the method. I have also worked on a generally applicable approach for calculating the target function in an automatic and non-arbitrary way. Traditionally, the target is set in an ad hoc way, while now sampling can be improved by 50% or more without extra effort. I have also used AWH to improve sampling in two biologically relevant applications. In one paper, we study the opening of a DNA base pair, which due to the stability of the DNA double helix only very rarely occurs spontaneously. We show that the probability of opening depends on both nearest-neighbor and longer-range sequence effect and furthermore structurally characterize the open states. In the second application the permeability and ammonia selectivity of the membrane protein aquaporin is investigated and we show that these functions are sensitive to specific mutations. / <p>QC 20171117</p>

Syftet med projektet är att analysera avvikelser mellan beräknad och uppmätt energianvändning för ett antal flerbostadshus i Stockholm. Detta är ett ämne som har uppmärksammats av myndigheter och företag, samtidigt som att energikraven blir ständigt tuffare. Av Sveriges totala energitillförsel används cirka 40 procent för drift och uppvärmning av byggnader, vilket innebär att byggsektorn bör arbeta aktivt med att minska energianvändningen och spela en stor roll i omställningen mot klimatneutralitet år 2045 för Sverige. Målet med projektet är att identifiera bidragande faktorer till avvikelser mellan energiberäkning och energianvändning för utvalda projekt, samt att ta fram förslag på förbättringsåtgärder som bidrar till förbättrade energiberäkningar och minskad energibehov. Metoden som används är att först analysera storlek på objekten för att sedan analysera den totala avvikelsen för dessa objekt på årsbasis och månadsbasis. Den totala avvikelsen analyseras på årsbasis, sedan kartläggs den månatliga förbrukningen i fyra poster: fastighetsel, värme, tappvarmvatten och hushållsel. En ny simulering och energiberäkning utförs på ett utvalt projekt med fokus riktad på orsaker till avvikelser. Resultatet visar att den mest bidragande faktorn till avvikelser är högre VVC-förluster, högre inomhustemperatur under uppvärmningssäsongen, lägre internvärme och högre ventilationsflöde. Vidare visar studien att det är möjligt att hitta orsakerna till avvikelse genom att enbart undersöka mätdata, om det är bra mätningsunderlag. / The purpose of the project is to analyze deviations between calculated and measured energy consumption for several apartment buildings in Stockholm. This is a topic that has been brought to the attention of authorities and companies, while at the same time the energy requirements are becoming increasingly tough. About 40 percent of Sweden's total energy supply is used for operation and heating of buildings, which means that the construction sector needs to work actively to reduce energy consumption and play a major role in the change towards climate neutrality in 2045 for Sweden. The aim of the project is to identify contributing factors to deviations between energy calculation and energy consumption for selected projects, and to develop proposals for improvement measures that contribute to improved energy calculations and reduced energy consumption. The method used is to first analyze the size of the objects and then to analyze the total deviation of these objects on a yearly and monthly basis. The total deviation is analyzed on an annual basis, then the monthly consumption is mapped into four items: real estate electricity, heating, domestic hot water and household electricity. A new simulation and energy calculation are performed on a selected project with a focus on causes of deviations. The result shows that the most contributing factor to deviations is higher VVC losses, higher indoor temperature during the heating season, lower internal heat and higher ventilation flow. Furthermore, the study shows that it is possible to find the causes of deviation by examining measurement data only if there is good measurement basis.

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Protein-ligand binding and protein allostery play a crucial role in cell signaling, cell regulation, and modern drug discovery. In recent years, experimental studies of protein structures including crystallography, NMR, and Cryo-EM are widely used to investigate the functional and inhibitory properties of a protein. On the one hand, structural classification and feature identification of the structures of protein kinases, HIV proteins, and other extensively studied proteins would have an increasingly important role in depicting the general figures of the conformational landscape of those proteins. On the other hand, free energy calculations which include the conformational and binding free energy calculation, which provides the thermodynamics basis of protein allostery and inhibitor binding, have proven its ability to guide new inhibitor discovery and protein functional studies. In this dissertation, I have used multiple different analysis and free energy methods to understand the significance of the conformational and binding free energy landscapes of protein kinases and other disease-related proteins and developed a novel alchemical-based free energy method, restrain free energy release (R-FEP-R) to overcome the difficulties in choosing appropriate collective variables and pathways in conformational free energy methods like umbrella sampling and metadynamics. / Chemistry

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Une étude expérimentale sur la faisabilité du procédé de dessalement par congélation sur les parois d'un tube cylindrique est présentée. Le procédé se décompose en deux étapes essentielles : la cristallisation suivie par le ressuage. Les cristallisations sont conduites à partir d'une solution stagnante ou agitée par un bullage d'air. Les paramètres opératoires clés sont la rampe de refroidissement et la salinité de l’eau traitée. Leur effet sur la salinité de la glace produite a été quantifié, dans les deux modes de fonctionnement, statique et agité. Le dispositif expérimental permet également de contrôler le gradient thermique à travers la couche de solution pour les cristallisations effectuées en statique. L'absence de gradient thermique et donc de courant de convection mène à des couches de glace très contaminées en sels. Les résultats combinant la cristallisation et le ressuage montrent que dans tous les cas, on peut obtenir de l'eau potable mais avec un rendement plus élevé et une durée réduite si la cristallisation a lieu en mode dynamique. Les conditions opératoires optimales sont proposées. La modélisation des transferts de matière et de chaleur à travers les couches de glace et de solution en régime diffusionnel et convectif a permis d’interpréter l’influence des paramètres opératoires des cristallisations opérées sans agitation. Enfin, l’évaluation économique du procédé complet de dessalement, basées sur des points de fonctionnement expérimentaux, indique que la consommation énergétique d’une petite installation pourrait être très faible en utilisant une machine frigorifique idéale fonctionnant entre l’unité de ressuage et l’unité de congélation. / An experimental study on the feasibility of sea water desalination by indirect freezing is presented. The whole process of desalination involves a freezing step, followed by a purification of the ice layer by sweating. Crystallization is led from quiescent solution or from agitated solution by air bubbling. The key operating parameters are the cooling rate, and solution salinity. Their effect on ice purity has been quantified in the static and agitated modes. The experimental setup enables as well the control of temperature gradient through the solution when the freezing step is conducted in the static mode. In the absence of temperature gradient and consequently the absence of convection currents, the ice layers formed are very contaminated in salts. The results combining crystallization and sweating show that in all cases, we can obtain drinking water, but with high yield and reduced process time when the crystallization is led in agitated mode. The optimal operating conditions are presented. The modelling of mass and heat transfers in the two phases in the diffusional and convective regimes has enabled the interpretation of the influence of operating parameters of crystallizations operated without agitation. At last, the economic evaluation of the whole desalination process, based on experimental operating points, indicates that energetic consumption of a small scale unit maybe low when using an ideal refrigerating machine which works between the sweating and the crystallization unities.