Cumulative Millisecond-Long Sampling for a Comprehensive Energetic Evaluation of Aqueous Ionic Liquid Effects on Amino Acid Interactions

Journal of Chemical Information and Modeling, vol. 63, pp. 281–298

Abstract

The interactions of amino acid side-chains confer diverse energetic contributions and physical properties to a protein’s stability and function. Various computational tools estimate the effect of changing a given amino acid on the protein’s stability based on parametrized (free) energy functions. When parametrized for the prediction of protein stability in water, such energy functions can lead to suboptimal results for other solvents, such as ionic liquids (IL), aqueous ionic liquids (aIL), or salt solutions. However, to our knowledge, no comprehensive data are available describing the energetic effects of aIL on intramolecular protein interactions. Here, we present the most comprehensive set of potential of mean force (PMF) profiles of pairwise protein–residue interactions to date, covering 50 relevant interactions in water, the two biotechnologically relevant aIL [BMIM/Cl] and [BMIM/TfO], and [Na/Cl]. These results are based on a cumulated simulation time of >1 ms. aIL and salt ions can weaken, but also strengthen, specific residue interactions by more than 3 kcal mol –1, depending on the residue pair, residue–residue configuration, participating ions, and concentration, necessitating considering such interactions specifically. These changes originate from a complex interplay of competitive or cooperative noncovalent ion–residue interactions, changes in solvent structural dynamics, or unspecific charge screening effects and occur at the contact distance but also at larger, solvent-separated distances. This data provide explanations at the atomistic and energetic levels for complex IL effects on protein stability and should help improve the prediction accuracies of computational tools that estimate protein stability based on (free) energy functions.

Authors 2

1. Till El Harrar Aachen Institute of Biotechnology

   RWTH Aachen University · Forschungszentrum Jülich · Jülich Supercomputing Centre · John von Neumann Institute for Computing

   Affiliation as printed

   Institute of Biotechnology, RWTH Aachen University, 52074 Aachen, Germany

   John von Neumann Institute for Computing (NIC), Jülich Supercomputing Centre (JSC), Institute of Biological Information Processing (IBI-7: Structural Biochemistry), and Institute of Bio- and Geosciences (IBG-4: Bioinformatics), Forschungszentrum Jülich GmbH, 52428 Jülich, Germany

2. Holger Gohlke corresponding

   Forschungszentrum Jülich · Heinrich Heine University Düsseldorf · Jülich Supercomputing Centre · John von Neumann Institute for Computing

   Affiliation as printed

   Institute for Pharmaceutical and Medicinal Chemistry, Heinrich Heine University Düsseldorf, 40225 Düsseldorf, Germany

   John von Neumann Institute for Computing (NIC), Jülich Supercomputing Centre (JSC), Institute of Biological Information Processing (IBI-7: Structural Biochemistry), and Institute of Bio- and Geosciences (IBG-4: Bioinformatics), Forschungszentrum Jülich GmbH, 52428 Jülich, Germany