A New Concept to Reveal Protein Dynamics Based on Energy Dissipation

Cheng-Wei Ma,An-Ping Zeng,Zhi-Long Xiu,Jie Zheng

doi:10.1371/journal.pone.0026453

Abstract

Protein dynamics is essential for its function, especially for intramolecular signal transduction. In this work we propose a new concept, energy dissipation model, to systematically reveal protein dynamics upon effector binding and energy perturbation. The concept is applied to better understand the intramolecular signal transduction during allostery of enzymes. The E. coli allosteric enzyme, aspartokinase III, is used as a model system and special molecular dynamics simulations are designed and carried out. Computational results indicate that the number of residues affected by external energy perturbation (i.e. caused by a ligand binding) during the energy dissipation process shows a sigmoid pattern. Using the two-state Boltzmann equation, we define two parameters, the half response time and the dissipation rate constant, which can be used to well characterize the energy dissipation process. For the allostery of aspartokinase III, the residue response time indicates that besides the ACT2 signal transduction pathway, there is another pathway between the regulatory site and the catalytic site, which is suggested to be the β15-αK loop of ACT1. We further introduce the term “protein dynamical modules” based on the residue response time. Different from the protein structural modules which merely provide information about the structural stability of proteins, protein dynamical modules could reveal protein characteristics from the perspective of dynamics. Finally, the energy dissipation model is applied to investigate E. coli aspartokinase III mutations to better understand the desensitization of product feedback inhibition via allostery. In conclusion, the new concept proposed in this paper gives a novel holistic view of protein dynamics, a key question in biology with high impacts for both biotechnology and biomedicine.

Highlights

As proteins are central to cellular function, researchers have sought to uncover the secrets of how these complex macromolecules execute such a fascinating variety of functions
According to the energy dissipation model, residues will response to the energy perturbation at different time points after the external energy input, forming the dynamic basis for signal transduction
It is believed that the difference in their response time depends on the intramolecular non-linear interactions which are based on the component and structure of the protein and is employed here to reflect the protein dynamical characteristics

Summary

Introduction

As proteins are central to cellular function, researchers have sought to uncover the secrets of how these complex macromolecules execute such a fascinating variety of functions. Proteins are inherently dynamical molecules that undergo structural fluctuations over a wide range of timescales, from femtoseconds to milliseconds or longer [1,2]. Structural fluctuations that occur on the fastest (femtosecond to picosecond) timescales permit the protein to sample a rugged energy landscape and facilitate slower, larger scale protein rearrangements that are responsible for modulating its biological function [3,4,5]. As a typical dynamical model for investigating the relationship between protein structure and function, allosteric proteins have attracted researchers’ attentions for decades (for reviews see [6,7,8,9]). Variant dynamical models have been proposed to discover the mechanism underlying the allosteric regulation. The aim of this work is to discover the energy dissipation model based on the allosteric process and to investigate this process by examining the characteristics of the energy dissipation model

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Conclusion