Development and Validation of the Quantum Mechanical Bespoke Protein Force Field.

Molecular mechanics force field parameters for macromolecules, such as proteins, are traditionally fit to reproduce experimental properties of small molecules, and thus, they neglect system-specific polarization. In this paper, we introduce a complete protein force field that is designed to be compatible with the quantum mechanical bespoke (QUBE) force field by deriving nonbonded parameters directly from the electron density of the specific protein under study. The main backbone and sidechain protein torsional parameters are rederived in this work by fitting to quantum mechanical dihedral scans for compatibility with QUBE nonbonded parameters. Software is provided for the preparation of QUBE input files. The accuracy of the new force field, and the derived torsional parameters, is tested by comparing the conformational preferences of a range of peptides and proteins with experimental measurements. Accurate backbone and sidechain conformations are obtained in molecular dynamics simulations of dipeptides, with NMR J coupling errors comparable to the widely used OPLS force field. In simulations of five folded proteins, the secondary structure is generally retained, and the NMR J coupling errors are similar to standard transferable force fields, although some loss of the experimental structure is observed in certain regions of the proteins. With several avenues for further development, the use of system-specific nonbonded force field parameters is a promising approach for next-generation simulations of biological molecules

How Atomic Level Interactions Drive Membrane Fusion: Insights From Molecular Dynamics Simulations

This project is focused on identifying the role of key players in the membrane fusion process at the atomic level with the use of molecular dynamics simulations. Membrane fusion of apposed bilayers is one of the most fundamental and frequently occurring biological phenomena in living organisms. It is an essential step in several cellular processes such as neuronal exocytosis, sperm fusion with oocytes and intracellular fusion of organelles to name a few. Membrane fusion is a frequent process in a living organism but is still not fully understood at the atomic level in terms of the role of various factors that play a crucial part in completion of membrane fusion. Two major factors that have been identified and studied experimentally are the protein Synaptotagmin and SNAREs. In addition, Ca2+ is known to play a crucial role in this process, however the exact mechanism of action is still unknown. Prime objective of this study is to understand these interactions and the role of Ca2 + in the process at the atomic level by carrying out molecular dynamics simulations. One of the primary calculations to perform is potential of mean force (PMF) between SYT and bilayer to analyze the effect of Ca2+ on their relative affinities. 1-octanol-water partition coefficient (log Kow) of a solute is a key parameter used in the prediction of a wide variety of complex phenomena such as drug availability and bioaccumulation potential of trace contaminants. Adaptive biasing force method is applied to calculate 1-octanol partition coefficients of n-alkanes and extended to other complex systems like ionic liquids, energetic materials and chemical warfare agents. Molecular dynamics simulations show that both domains of SYT-1, C2A and C2B, once calcium bound, insert into the lipid bilayer composed of anionic phospholipids. In contrast, no insertion is observed when the domains do not have bound calcium or when the bilayer is not charged negative. Electrostatic interactions play an important role in this insertion process. Effect of calcium binding to the C2A and C2B domain on the overall electrostatics of the protein was studied by generating the ESP maps. Negative potential on the Calcium binding pocket transforms into positive potential once calcium is attached to those sites. Interaction of this positive potential surface with the negatively charged bilayer acts as a driving force for protein insertion into the bilayer. In addition, adaptive biasing force method has emerged as a powerful tool for prediction of 1-octanol water partition coefficients and is successfully implemented and optimized for n-alkanes and extended to the systems of ionic liquids, energetic materials and chemical warfare agents for which 1-octanol water partition coefficient is either not known or is difficult to measure via experimental methods

Advances in Computational Solvation Thermodynamics

The aim of this thesis is to develop improved methods for calculating the free energy, entropy and enthalpy of solvation from molecular simulations. Solvation thermodynamics of model compounds provides quantitative measurements used to analyze the stability of protein conformations in aqueous milieus. Solvation free energies govern the favorability of the solvation process, while entropy and enthalpy decompositions give insight into the molecular mechanisms by which the process occurs. Computationally, a coupling parameter λ modulates solute-solvent interactions to simulate an insertion process, and multiple lengthy simulations at a fixed λ value are typically required for free energy calculations to converge; entropy and enthalpy decompositions generally take 10-100 times longer. This thesis presents three advances which accelerate the convergence of such calculations: 1) Development of entropy and enthalpy estimators which combine data from multiple simulations; 2) Optimization of λ schedules, or the set of parameter values associated with each simulation; 3) Validation of Hamiltonian replica exchange, a technique which swaps λ values between two otherwise independent simulations. Taken together, these techniques promise to increase the accuracy and precision of free energy, entropy and enthalpy calculations. Improved estimates, in turn, can be used to investigate the validity and limits of existing solvation models and refine force field parameters, with the goal of understanding better the collapse transition and aggregation behavior of polypeptides

Understanding enhanced oil recovery (EOR) in sandstone reservoirs: the role of redox changes in clay minerals on wettability

A great body of research has been focused on understanding enhanced oil recovery in mature sandstone reservoirs. The benefit of further producing such mature fields is indisputable since the natural-driven oil recovery of the oil initially in place can vary from <5% to 50%, in the best-case scenario. The enhanced oil recovery methods, such as CO2 injection, steam injection, surfactant injection etc., have been established through the years, with researchers proposing mechanisms that can explain the additional oil recovery. The following pages of this thesis explore in more detail the low salinity water flooding (LSWF), a method that has gained significant ground the recent years, due to the low costs of implementation. Many mechanisms have been proposed since the 1950's, when first observations were made, with more light being shed since the late 1990's, continuously to present day. The experimental work of this PhD project focused on examining reduction-oxidation (redox) processes during oil recovery upon EOR implementation. This was approached by using iron-bearing clay minerals, with various iron content, as proxies of iron phases present in the reservoir rock. First, the wettability of those clay minerals, such as natural occurring nontronite and illite, was explored via clay mineral films, measuring the contact angle of crude oil and DI water, under reduced and oxidised conditions, with reduced clay films, exhibiting more water-wet surfaces. Then, the hydration and structural changes of a nontronite clay mineral was established with infrared spectroscopy (IR). At these experiments, the saturating cation was manipulated by clay mineral treatment, acquiring homoionic Na+, Ca2+ and K+ samples of nontronite, allowing the isolation of hydration effects and other clay mineral / cation interactions. Those IR measurements revealed a more hydrated state under partial reduction, and stronger clay mineral/ cation interaction under (partially) reduced conditions (N-IR, M-IR). Significant spectral alterations were also observed at the F-IR range, upon clay mineral reduction, with minimum effects due to cation saturation and relative humidity induced. Lastly, the thermodynamics of cation exchange reactions, using two Na+-saturated nontronites and a Na+-saturated montmorillonite, was attempted to be quantified. Two different reactions were considered for all three minerals: clay mineral- Na-->Ca and Na-->K. These experiments, conducted under fully reduced conditions, showed that the inverse of the Na-->Ca reaction is favoured (Ca favoured with ΔG <0), which supports the basic theory of LSWF, as sodium is considered a key factor for LSWF positive effect, but also how cation exchange, under such redox conditions, are exhibiting hysteresis, a key observation for better understanding such processes on clay minerals, across disciplines

Rism-based pressure-dependent computational spectroscopy

Spectroscopic measurements are an indispensable tool in chemical analysis; even under extreme conditions such as high hydrostatic pressures, they can provide valuable insights. Theoretical methods that can reliably reproduce observables in solution can be used to validate the obtained results. A common theoretical model is the Reference Interaction Site Model (RISM), which was used in this work. In the first part, a previously developed method for calculating IR frequencies with the embedded cluster(EC)-RISM under equilibrium conditions was extended to non-equilibrium thermodynamics for IR spectroscopy. The pressure-dependent IR frequency shifts of TMAO and the cyanide anion were investigated as model systems. Furthermore, EC-RISM was used here for the first time to calculate EPR observables at ambient conditions. First, experiments with the geometrically optimized structure showed that EC-RISM gives significantly better results than a standard continuum calculation despite a large deviation from the experiment. A significant improvement in the direction of the experimental values was achieved by using a large number of snapshots from an ab initio molecular dynamics simulation (AIMD) instead of a single geometry. In general, in the context of the theoretical description of high-pressure effects on proteins, the critical question can be raised whether using force fields parameterized for ambient conditions is appropriate for high-pressure conditions. To answer this question, the pressure dependence of the peptide backbone was investigated in the third part, and the small molecules N-methyl acetamide (NMA) and Ac-Gly/Ala-NHMe were used as model systems. In this work, it was shown that EC-RISM is a suitable method of choice for the calculation of spectroscopic observables in solution. Especially when non-ambient conditions are to be examined, EC-RISM shows its strength since it is relatively easily extensible, e.g., high-pressure environments

Physico-chemical aspects of water-based emulsion paints

An investigation has been performed with a view to elucidating the factors affecting storage stability and particle flocculation during drying of a water-based emulsion paint, by using a model system of polyvinyl acetate latex and a rutile pigment, where the latex was stabilized with sodium dodecyl sulphate and the pigment with polyphosphate (sodium hexametaphosphate). In particular, the studies have concentrated on the influences of sodium dodecyl sulphate (SDS), and polyphosphate on particle stability and film formation. It has been shown that sodium dodecyl sulphate (SDS) improves the stability of the latex and pigment, while polyphosphate improves pigment stability but reduces latex stability. [Continues.

Chemical heterogeneity of glaciofluvial deposits: Outcrop study and implications for reactive transport

Spatial variations in the reactive properties of geologic systems and their influence on contaminant transport are poorly understood. Consequently, an outcrop study was conducted in a glaciofluvial deposit in Deerfield, New Hampshire in order to: (1) identify the sediment properties controlling heavy metal adsorption, (2) evaluate the extent to which geologic information can be used to characterize their spatial variation, and (3) assess the impact of spatial variations on heavy metal transport. Four hundred seventy-six, spatially-located sediment samples were collected from an eight square meter vertical exposure of outwash sands and gravels. Lithologic facies were mapped on outcrop photographs. Sample color, permeability, porosity, grain size, surface area, lead (Pb2+) sorption, carbon content, magnetic mineral content, and dithionite citrate-extractable iron, manganese, and aluminum content were measured in the laboratory. Fifty-seven percent of the variation in Pb2+ sorption can be explained by a linear combination of sediment permeability and extractable iron, manganese, and aluminum, indicating that Pb2+ sorption is controlled by (hydr)oxide grain coatings. Reactive surface area, estimated from sample grain size and (hydr)oxide mass together with observations of grain coating morphology and numerical abundance, accounts for 65 percent of the sorption variation. Three sorption-related properties: permeability, extractable iron, and extractable manganese are strongly related to sediment facies and/or color and thus can be mapped over a wide range of spatial scales. Differences in the geometries of iron and manganese enrichment, petrographic observations, and SEM-EDS analyses indicate the grain coatings originated from the post-depositional weathering of biotite and garnet, coupled with local, redox-driven redistribution of the liberated iron and manganese. Numerical simulations show that spatial variations in (hydr)oxide grain coatings increase plume mobility and dispersion when the spatial scale of the heterogeneity is similar to the scale of the problem. Overall, the outcrop study findings suggest that Pb2+ partition coefficients can be estimated from relatively simple and inexpensive measurements of permeability and dithionite-citrate extractable metals. The results further suggest that information regarding sediment facies and color can help produce more efficient and geologically realistic descriptions of chemical heterogeneity