Dynamic Allostery in the Methionine Repressor Revealed by Force Distribution Analysis

Abstract

Many fundamental cellular processes such as gene expression are tightly regulated by protein allostery. Allosteric signal propagation from the regulatory to the active site requires long-range communication, the molecular mechanism of which remains a matter of debate. A classical example for long-range allostery is the activation of the methionine repressor MetJ, a transcription factor. Binding of its co-repressor SAM increases its affinity for DNA several-fold, but has no visible conformational effect on its DNA binding interface. Our molecular dynamics simulations indicate correlated domain motions within MetJ, and quenching of these dynamics upon SAM binding entropically favors DNA binding. From monitoring conformational fluctuations alone, it is not obvious how the presence of SAM is communicated through the largely rigid core of MetJ and how SAM thereby is able to regulate MetJ dynamics. We here directly monitored the propagation of internal forces through the MetJ structure, instead of relying on conformational changes as conventionally done. Our force distribution analysis successfully revealed the molecular network for strain propagation, which connects collective domain motions through the protein core. Parts of the network are directly affected by SAM binding, giving rise to the observed quenching of fluctuations. Our results are in good agreement with experimental data. The force distribution analysis suggests itself as a valuable tool to gain insight into the molecular function of a whole class of allosteric proteins.

Long-Range Conformational Transition of a Photoswitchable Allosteric Protein: Molecular Dynamics Simulation Study

“…For example, a number of network models have been proposed that may reflect the intramolecular signal propagation. This includes networks based on the statistical analysis of evolutionary conserved sequences, 30,31 on vibrational energy flow 32,33 or residue-residue interaction energies, 34,35 on C α -C α correlations of low-frequency normal modes, 36 on the linear response to residue perturbation, 37,38 on coupled side-chain fluctuations, 39 on a force distribution analysis, 40 and on information-theoretical approaches. [41][42][43] In the present paper, we take yet another approach, i.e.…”

A consistent S-Adenosylmethionine force field improved by dynamic Hirshfeld-I atomic charges for biomolecular simulation

“…As comparison we performed a second simulation with the parameters recently reported by Stacklies et al [17] using the standard GAFF values. We first focus on the beta(H14,H15)-methyl(H18-H20) distance being the most sensitive to the newly obtained dihedrals parameters.…”

“…Nevertheless, the sulfonium group is not represented in the force field since AMBER99 lacks a trivalent sulfur atom type. Parameters describing C-S bond stretching, C-S-C angle bending and C-S-C-H dihedral angle were taken from Stacklies et al [17], as they reproduced ab initio potential energy curves accurately. The sulfur atom type was set to ''S4'' that is used for all sulfur containing molecules in the GAFF force field [21].…”

“…Most of these proteins have been subject of recent computational studies on different aspects of their function as the enzymatic activity [16] and allosteric binding [17]. Recently, also the interaction of AdoMet with RNA was addressed computationally to study the kinetic trapping of RNA in the SAM-I Riboswitch [18,19].…”

Mapping the intramolecular signal propagation pathways in protein using Bayesian change point analysis of atomic motions

“…There are several examples of successful mapping of the allosteric pathways in proteins based on their structure, evolutionary conservation, modeling the protein as a network and considering the residue connectivity, and inter-atom force distribution analysis (Chen et al, 2007;Chennubhotla et al, 2008;Stacklies et al, 2009;Lu et al, 2010;Selvaratnam et al, 2011;…”