(214z) A Molecular Dynamics Study of the Effects of Ionic Liquids On Human Serum Albumin

Ionic liquids (IL), which are organic salts that are liquid below 100° C, have been studied as a unique solvent for biologically relevant molecules including proteins. Research has shown that ionic liquids hold promise as a biological solvent in a few cases. First, they solvate recalcitrant solutes like cellulosic biomass. Second, they can affect the function of enzymes in order to bring about unique reactions. Third, they can stabilize proteins during long-term storage or facilitate refolding of proteins. One class of model protein that has been studied for its stability in ILs is serum albumin, a ubiquitous protein that facilitates the transport of molecules through the bloodstream. These studies have provided insights into the effects of ionic liquids on the function, structure, and dynamics of serum albumin, but most studies lack a molecular level understanding of the protein-solvent interaction. We have employed molecular dynamics with enhanced sampling techniques in order to compliment the breadth of published work and to gain molecular level insight into this complex interaction.

We conducted molecular dynamics simulations to test the effects of imidazolium- and choline-based ILs in binary mixtures with water on the structure and dynamics of human serum albumin. The dynamic fluctuations of the protein are dampened by the presence of IL as measured by root mean squared fluctuation. Principle component analysis shows differences in the slow modes of motion depending on the composition of the solvent. Serum albumin contains several well defined domains that are held together by disulfide bridges that cause the protein to adopt a heart-shaped conformation. Essential dynamics coarse graining was employed to determine if the location of each domain remains the same in each solvent. Structuring of the IL and water around the protein was analyzed to determine preferential interaction sites and the effects of these interactions. All of the results show qualitative agreement with experimental observations.

One specific study indicates that loop 1 of domain I in human serum albumin displays high rates of denaturation in imidazolium-based ILs as measured by fluorescence spectroscopy. We employ well-tempered metadynamics in order to study this specific loop. Well-tempered metadynamics is an enhanced sampling technique in which a small time-dependent bias potential is added to a collective variable in order to discourage the system from revisiting previously explored conformations. Solvent dependent differences in the free energy of the transition of this loop from its folded to unfolded state are observed.