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Computational Physical Chemistry and Biochemistry

We study the stability of chemical and biochemical systems by investigating their dynamics using computer modelling. Computer simulations is a powerful tool in exploring microscopic details of physical and chemical phenomena. Sizes of systems that are investigated range from small clusters to systems containing hundreds of thousand atoms. We focus on the development and application of Molecular Dynamics and Monte Carlo techniques to study rare event dynamics. These critical events, that are usually identified with the transition state of the process, are a bottle-neck in the simulations of a variety of systems of chemical and biological interest. The systems are modelled at the atomic scale using different levels of description in order to capture features defining the properties of the systems.

Development of methods for rare event dynamics

Chemical reactions in solution, nucleation procesesses in phase transitions, conformational changes of macromolecules are examples of chemical processes that occur on long time scales. Such time scales cannot be easily accessed using direct Molecular Dynamics techniques using presently available computer resources. In order to solve these problems we develop new effective methods of the configurational space sampling.
Regions of the phase diagram in the system of $\xi = \lambda/L$ and $L/R$ coordinates. Contiguous lines correspond to constant values of the interaction parameter $B_{\mathrm{ex}}$. The gray region in all subplots indicates location of the restricted domain (see details in the text). The plot shows an overall view of the minima of the droplet energy. Representative snapshots of simulations of charged PEG in water droplets that correspond to the various regions of the phase diagram are also shown.
Using chemical insight and results of direct computer modelling we investigate a reaction coordinate (or a set of such coordinates) that is pertinent to the physical process. The phenomena that are studied are complex and the degrees of freedom of the environment, for example the solvent, has to be taken into account when choosing the reaction coordinate. Reversible work profiles and sampling of trajectories initiated at the transition state reveal the reaction mechanism and allows for the computation of the rate. We have indentified new problems for the application of methods of activated processes, such as the fragmentation of charged droplets at a low ratio of the square of the charge to volume of the droplet; extrusion of macromolecules from droplets. In these systems we have developed new reaction coordinates. We apply advanced sampling techniques such as Multiple Replica Repulsion and transition path sampling to calculate free energy profiles and associated equilibrium constants for non-covalently bound complexes involving nucleic acids, proteins and other macromolecules.

Stability of charged droplets with applications in electrospray ionization

My research group uses molecular simulations and analytical methods combined with analysis of experimental data as principal techniques to study the various facets of the vast world that is cluster and droplet environment. The droplets in question are composed of solvent and charge carriers that may be simple ions such as sodium, potassium, macromolecular ions (protonated peptides, charged polyethylene glycol) and complexes of macromolecules such as small interfering RNA (si-RNA), dsDNA or complexes of proteins. Highly charged droplets present atypical chemical environment with distinct properties characterized by high ionic concentrations. The questions that we pose are on the interactions of ions with macromolecules, stability of complexes of macrolecules and creation of assembled structures in the droplet environment. The questions are intimately connected to the concomitant topics of solvation of neutral and charged macromolecules in clusters and droplets; chemical reactions between charge carriers and macromolecules; release of macromolecular ions from droplets; evaporation of droplets; role of acidity in the charge states of proteins; clustering/declustering of peptides in droplets. In order to understand the factors that differentiate the behaviour of the macromolecules in the droplet environment vs. the bulk solution, we also investigate the charge states and conformational changes in the bulk solution. The studies of charged macromolecules in bulk and droplet environments perform central role in such diverse subjects such as poly-electrolytes in solution (e.g. DNA, proteins); and experimental methods such as electrospray ionization (ESI) and ion-mobility spectroscopy (IMS) where jets of charged nanodroplets with macromolecules is a critical intermediate state. Our computational studies provide the molecular understanding in experiments that use electrospray ionization (ESI). Examples of such experiments are found in the usage of ESI in transfer of analytes from bulk solution into the gas phase for mass spectrometry (MS) analysis, deposition of materials and creation of nanoparticles with controlled morphologies. The outcome of these applications is vast. They lead to the understanding of the interactions among biological molecules, discovery of pharmaceuticals, increased security in transportation by detection of explosives in the airports, efficient chemical analysis, industry production.

Star-shaped droplets

A 12-point star aqueous droplet composed of water and a central macroion. Examples of macroions with high charge are proteins and nucleic acids .
An important finding of our research has been the formation of ``star''-shaped droplet morphologies in the presence of a central macroion [S. Consta, Journal of Physical Chemistry B v. 114, pp. 5263--5268 (2010); M. In Oh et al., Soft Matter v. 13, pp. 8781-8795 (2017)]. This finding led us to think whether we can generate solid highly non-convex colloids by adjusting the charge state of the central macroion. We analyzed distinct features in the structure of the star-shaped nano-droplets using molecular modeling. We also examined whether a different level of modelling, continuum modelling can reproduce the star-shapes found by molecular modelling. This study unpredictably revealed important physical questions related to the energetic components that enter a continuum description of charged droplets, the relation of the number of the points in the stars to the famous J. J. Thomson problem of electrons in a spherical cavity and the relation between the cornerstone structure of Taylor cones in liquid jets to the angles in the rays of the stars. Our on-going research on answering these questions may shed light into the understanding of the structures of solid star-shaped nano-particles star-shaped, protein droplets in solution found in experiments and the structures developed in the growth of snowflakes on charged centers.

Modeling the stability of non-covalent protein and nucleic acid complexes and assemblies

The relation between the gas phase and the solvation phase structures of protein assemblies and nucleic acids detected by native mass spectrometry has been a recurrent question for over two decades. The same question arises when the equilibrium constants of non-covalent complexes are determined by using electrospray ionization mass spectrometry. The non-covalent complexes may be nucleic acids, proteins, and their combination, as well as protein-ligand complexes. The ligands include drug molecules, peptides, oligonucleotides, carbohydrates, and lipids. The non-covalent complexes of biological molecules play a fundamental role in virtually all cellular functions. For instance, transient protein complexes are responsible for signaling and regulatory mechanisms in a cell and nucleic acids store genetic information. The dissociation constant of a complex ranges from nanomolar concentration for drug-protein interactions to millimolar concentration for protein complexes participating in signalling pathways. Using double-stranded DNA with different nucleotide sequences one may design and investigate complexes with different values of the equilibrium constant. In our research we address fundamental questions of the stability of complexes of macromolecules that cannot readily detected in experiments. We have performed the first simulations of computing the effect in the equilibrium constant of possible protein complex dissociation during the transfer of protein complexes from the bulk solution to the gaseous state for mass spectrometry analysis [M. In Oh and S. Consta, Journal of Physical Chemistry Letters v. 8, pp. 80-85 (2017)]. We have also performed the the first simulations of the effect of the droplet environment in the stability of nucleic acids [M. Sharawy and S. Consta, Physical Chemistry Chemical Physics v. 17, pp. 25550-25562 (2015)]. Currently, we study the stability of nucleic acids and protein complexes in bulk solution and we extend further our studies in droplets.

Nanopores and confinement

Zeolite molecular sieves are microporous aluminosilicate framework materials containing channels and cavities with molecular dimensions . They are widely used in industry as ion-exchangers, sorbents and catalysts. In the last decade, the increased awareness of the environmental hazards that are caused by chlorinated halocarbons has led to the development of new separation and catalytic conversion processes that utilize zeolites. The effectiveness of zeolites is based on its porous nature and on the distinct interactions between the zeolitic hosts and adsorbed guest species. Among the chemical and physical transformations that a zeolite may induce to a guest molecule, in our research we consider conformational changes of the adsorbed guest molecule due to electrostatic interactions with the zeolite framework. The existence of different conformers of the guest molecule is one of the factors that affects the separation efficiencies of zeolites. Different conformers can have different electric dipole and quadrupole moments, and these molecular properties can affect the heats of adsorption and diffusion of the guest molecules inside the zeolite hosts. In the figures conformations of 1,1,2-trichloro ethane (TCE) in Faujasite (FAU) structure zeolites including sodium Y (Na-Y) and siliceous Y (Si-Y) are shown.