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Thermodynamics of Hydrophobic Amino Acids in Solution: A Combined Experimental-Computational Study.

ABSTRACT: We present a joint experimental-computational study to quantitatively describe the thermodynamics of hydrophobic leucine amino acids in aqueous solution. X-ray scattering data were acquired at a series of solute and salt concentrations to effectively measure interleucine interactions, indicating that a major scattering peak is observed consistently at q = 0.83 Å-1. Atomistic molecular dynamics simulations were then performed and compared with the scattering data, achieving high consistency at both small and wider scattering angles (q = 0-1.5 Å-1). This experimental-computational consistence enables a first glimpse of the leucine-leucine interacting landscape, where two leucine molecules are aligned mostly in a parallel fashion, as opposed to antiparallel, but also allows us to derive effective leucine-leucine interactions in solution. Collectively, this combined approach of employing experimental scattering and molecular simulation enables quantitative characterization of effective intermolecular interactions of hydrophobic amino acids, critical for protein function and dynamics such as protein folding.

SUBMITTER: Song L

PROVIDER: S-EPMC5256481 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature

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Thermodynamics of Hydrophobic Amino Acids in Solution: A Combined Experimental-Computational Study.

Song Lingshuang L Yang Lin L Meng Jie J Yang Sichun S

The journal of physical chemistry letters 20170103 2

We present a joint experimental-computational study to quantitatively describe the thermodynamics of hydrophobic leucine amino acids in aqueous solution. X-ray scattering data were acquired at a series of solute and salt concentrations to effectively measure interleucine interactions, indicating that a major scattering peak is observed consistently at q = 0.83 Å<sup>-1</sup>. Atomistic molecular dynamics simulations were then performed and compared with the scattering data, achieving high consis ...[more]

PMID: 28033710

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Project description:A major current challenge for drug design efforts focused on protein kinases is the development of drug resistance caused by spontaneous mutations in the kinase catalytic domain. The ubiquity of this problem means that it would be advantageous to develop fast, effective computational methods that could be used to determine the effects of potential resistance-causing mutations before they arise in a clinical setting. With this long-term goal in mind, we have conducted a combined experimental and computational study of the thermodynamic effects of active-site mutations on a well-characterized and high-affinity interaction between a protein kinase and a small-molecule inhibitor. Specifically, we developed a fluorescence-based assay to measure the binding free energy of the small-molecule inhibitor, SB203580, to the p38α MAP kinase and used it measure the inhibitor's affinity for five different kinase mutants involving two residues (Val38 and Ala51) that contact the inhibitor in the crystal structure of the inhibitor-kinase complex. We then conducted long, explicit-solvent thermodynamic integration (TI) simulations in an attempt to reproduce the experimental relative binding affinities of the inhibitor for the five mutants; in total, a combined simulation time of 18.5 μs was obtained. Two widely used force fields - OPLS-AA/L and Amber ff99SB-ILDN - were tested in the TI simulations. Both force fields produced excellent agreement with experiment for three of the five mutants; simulations performed with the OPLS-AA/L force field, however, produced qualitatively incorrect results for the constructs that contained an A51V mutation. Interestingly, the discrepancies with the OPLS-AA/L force field could be rectified by the imposition of position restraints on the atoms of the protein backbone and the inhibitor without destroying the agreement for other mutations; the ability to reproduce experiment depended, however, upon the strength of the restraints' force constant. Imposition of position restraints in corresponding simulations that used the Amber ff99SB-ILDN force field had little effect on their ability to match experiment. Overall, the study shows that both force fields can work well for predicting the effects of active-site mutations on small molecule binding affinities and demonstrates how a direct combination of experiment and computation can be a powerful strategy for developing an understanding of protein-inhibitor interactions.

Dataset Information

Thermodynamics of Hydrophobic Amino Acids in Solution: A Combined Experimental-Computational Study.

Publications

Thermodynamics of Hydrophobic Amino Acids in Solution: A Combined Experimental-Computational Study.

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