Multistage modeling of protein dynamics with monomeric Myc oncoprotein as an example

Abstract

We propose to combine a mean field approach with all atom molecular dynamics (MD), 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 Cα 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 Cα 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 α-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.

Mapping Hidden Residual Structure within the Myc bHLH-LZ Domain Using Chemical Denaturant Titration

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Phenotypic Plasticity and Cell Fate Decisions in Cancer: Insights from Dynamical Systems Theory

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Application of topological soliton in modeling protein folding: Recent progress and perspective

“…Then some examples of successful applications will be presented, including the folding simulations for both ordered and disordered proteins, the multi-scale simulations by combining with the all-atom MD, the characteristic analysis of dynamic conformations. [35][36][37][38] In the last section, we will bring forward a perspective on the theory and possible applications of topological soliton in protein researches.…”