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Biomolecular Simulations on Different Time- and Length-Scales

Biomolecular Simulations on Different Time- and Length-Scales

Datum: 16. Juni 2016 16:00

Ort: Allmandring 3, Seminarraum 1.079

Veranstalter: ICP

Biomolecular Simulations on Different Time- and Length-Scales

Lars Schäfer, Universität Bochum

Two key challenges of simulating biomolecular systems are i) the typically large system sizes required, and ii) the long time-scales involved. These two aspects are often closely intertwined, since larger systems usually have longer correlation and relaxation times, thus aggravating the computational challenges. In the talk, I will discuss two case examples from our recent work to illustrate how the above challenges can be overcome.

In the first example, coarse-grained (CG) and all-atom MD simulations are combined to study lipid nanodiscs [1]. The computationally efficient CG force field is used to directly simulate the slow (multi- microsecond) self-assembly process, whereas the subsequent all-atom simulations yield accurate structural and dynamic properties, such as lipid order parameters and entropies. In addition, the adopted sequential dual-scale approach enables a quantitative comparison of the all-atom and coarse-grained results.

The second part of the talk will focus on the tapasin-MHC I complex as a prime example for protein- protein association [2,3]. Conventional simulation approaches involve approximations such as treating the proteins as rigid bodies, describing the systems at a coarse-grained representation, or modeling the solvent as a dielectric continuum. Indeed, we found that for the tapasin-MHC I encounter, any of these approximations severely hampers the accuracy of the results. We thus used all-atom MD simulations in explicit solvent to study the protein association, which takes place on the multi-microsecond time scale. The obtained structure of the complex, which was hitherto unknown at the atomic level, enables us to address open questions concerning the biological function of the tapasin-MHC I complex, which is a key player in the mammalian adaptive immune system.

In the final part of the talk, if time permits, I will briefly discuss current methodological challenges involved with hybrid all-atom/coarse-grained approaches [4,5].

[1] A. Debnath, L. V. Schäfer. Structure and Dynamics of Phospholipid Nanodiscs from All-Atom and Coarse-Grained Simulations, J. Phys. Chem. B, 2015, 119 (23), 6991-7002.

[2] G. Fleischmann, O. Fisette, C. Thomas, R. Wieneke, F. Tumulka, C. Schneeweiss, S. Springer, L. V. Schäfer, R. Tampé. Mechanistic Basis for Epitope Proofreading in the Peptide Loading Complex, J. Immunol., 2015, 195 (9), 4503-4513.

[3] O. Fisette, S. Wingbermühle, R. Tampé, L. V. Schäfer. Molecular Mechanism of Peptide Editing in the Tapasin-MHC I Complex, Sci. Rep., 2016, 6, 19085.

[4] T. A. Wassenaar, H. I. Ingolfsson, M. Prieß, S. J. Marrink, L. V. Schäfer. Mixing Martini: Electrostatic Coupling in Hybrid Atomistic/Coarse-Grained Biomolecular Simulations, J. Phys. Chem. B, 2013, 117 (13), 3516-3530.

[5] A. B. Kuhn, S. M. Gopal, L. V. Schäfer. On Using Atomistic Solvent Layers in Hybrid All-Atom / Coarse-Grained Molecular Dynamics Simulations, J. Chem. Theory Comput., 2015, 11 (9), 4460-4472.

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