Molecular modelling of the mass density of single proteins

Abstract

Using molecular dynamics (MD) simulations, the density of single proteins and its temperature dependence was modelled starting from the experimentally determined protein structure and a generic, transferable force field, without the need of prior parameterization. Although all proteins consist of the same 20 amino acids, their density in aqueous solution varies up to 10% and the thermal expansion coefficient up to twofold. To model the protein density, systematic MD simulations were carried out for 10 proteins with a broad range of densities (1.32–1.43 g/cm³) and molecular weights (7–97 kDa). The simulated densities deviated by less than 1.4% from their experimental values that were available for four proteins. Further analyses of protein density showed that it can be essentially described as a consequence of amino acid composition. For five proteins, the density was simulated at different temperatures. The simulated thermal expansion coefficients ranged between 4.3 and 7.1 × 10⁻⁴ K⁻¹ and were similar to the experimentally determined values of ribonuclease-A and lysozyme (deviations of 2.4 and 14.6%, respectively). Further analyses indicated that the thermal expansion coefficient is linked to the temperature dependence of atomic fluctuations: proteins with a high thermal expansion coefficient show a low increase in flexibility at increasing temperature. A low increase in atomic fluctuations with temperature has been previously described as a possible mechanism of thermostability. Thus, a high thermal expansion coefficient might contribute to protein thermostability.

Keywords:

• molecular dynamics (MD) simulation
• thermal expansion coefficient
• amino acid composition
• flexibility
• thermostability

Acknowledgements

We thank the High Performance Computing Center Stuttgart for providing access to their computer facilities, and the Deutsche Forschungsgemeinschaft (SFB716) for financial support.

Notes

1With crystal water.

2Without crystal water.

3For one Candida antarctica lipase B molecule/box.

4For eight Candida antarctica lipase B molecules/box.

5For the monomer.

6For the dimer.