Towards multistage modelling of protein dynamics with monomeric Myc oncoprotein as an example

TL;DR

This paper introduces a multistage modeling approach combining mean field theory and molecular dynamics to study long-timescale protein dynamics with atomic detail, exemplified by the intrinsically disordered Myc oncoprotein.

Contribution

It develops a novel multistage algorithm integrating mean field and all-atom MD to model protein folding and dynamics over long periods with high precision, applied to Myc.

Findings

Myc monomer is dynamically oscillating between conformations.

The initial structure is unstable and has a degenerate ground state landscape.

Oscillatory motions resembling Davydov's soliton are observed during MD simulations.

Abstract

We propose to combine a mean field approach with all atom molecular dynamics into a multistage algorithm that can model protein folding and dynamics over very long time periods yet with atomic level precision. As an example we investigate an isolated monomeric Myc oncoprotein that has been implicated in carcinomas including those in colon, breast and lungs. Under physiological conditions a monomeric Myc is presumed to be an example of intrinsically disordered proteins, that pose a serious challenge to existing modelling techniques. We argue that a room temperature monomeric Myc is in a dynamical state, it oscillates between different conformations that we identify. For this we adopt the C-alpha backbone of Myc in a crystallographic heteromer as an initial Ansatz for the monomeric structure. We construct a multisoliton of the pertinent Landau free energy, to describe the C-alpha profile with ultra high precision. We use Glauber dynamics to resolve how the multisoliton responds to repeated increases and decreases in ambient temperature. We confirm that the initial structure is unstable in isolation. We reveal a highly degenerate ground state landscape, an attractive set towards which Glauber dynamics converges in the limit of vanishing ambient temperature. We analyse the thermal stability of this Glauber attractor using room temperature molecular dynamics. We identify and scrutinise a particularly stable subset in which the two helical segments of the original multisoliton align in parallel, next to each other. During the MD time evolution of a representative structure from this subset, we observe intermittent quasiparticle oscillations along the C-terminal alpha-helix, some of which resemble a translating Davydov's Amide-I soliton. We propose that the presence of oscillatory motion is in line with the expected intrinsically disordered character of Myc.