Mechanism for the Unfolding of the TOP7 Protein in Steered Molecular Dynamics Simulations as Revealed by Mutual Information Analysis

We employed mutual information (MI) analysis to detect motions affecting the mechanical resistance of the human-engineered protein Top7. The results are based on the MI analysis of pair contact correlations measured in steered molecular dynamics (SMD) trajectories and their statistical dependence on global unfolding. This study is the first application of the MI analysis to SMD forced unfolding, and we furnish specific SMD recommendations for the utility of parameters and options in the TimeScapes package. The MI analysis provided a global overview of the effect of perturbation on the stability of the protein. We also employed a more conventional trajectory analysis for a detailed description of the mechanical resistance of Top7. Specifically, we investigated 1) the hydropathy of the interactions of structural segments, 2) the H2O concentration near residues relevant for unfolding, and 3) the changing hydrogen bonding patterns and main chain dihedral angles. The results show that the application of MI in the study of protein mechanical resistance can be useful for the engineering of more resistant mutants when combined with conventional analysis. We propose a novel mutation design based on the hydropathy of residues that would stabilize the unfolding region by mimicking its more stable symmetry mate. The proposed design process does not involve the introduction of covalent crosslinks, so it has the potential to preserve the conformational space and unfolding pathway of the protein.

Download Full-text

Atomistic Mechanisms of Human TRPA1 Activation By Electrophile Irritants Through Molecular Dynamics Simulation and Mutual Information Analysis

10.21203/rs.3.rs-1138621/v1 ◽

2021 ◽

Author(s):

Matthew Habgood ◽

David Seiferth ◽

Afroditi-Maria Zaki ◽

Irfan Alibay ◽

Philip Biggin

Keyword(s):

Molecular Dynamics ◽

Mutual Information ◽

Binding Sites ◽

Wide Spectrum ◽

Covalent Binding ◽

Dynamics Simulation ◽

Binding Modes ◽

Information Analysis ◽

Dynamics Simulations ◽

Mutual Information Analysis

Abstract The ion channel TRPA1 is a promiscuous chemosensor, with reported response to a wide spectrum of noxious electrophilic irritants, as well as cold, heat, and mechanosensation. It is also implicated in the inception of itch and pain and has hence been investigated as a drug target for novel analgesics. The mechanism of electrophilic activation for TRPA1 is therefore of broad interest. TRPA1 structures with the pore in both open and closed states have recently been published as well as covalent binding modes for electrophile agonists. However, the detailed mechanism of coupling between electrophile binding sites and the pore remains speculative. In addition, while two different cysteine residues (C621 and C665) have been identified as critical for electrophile bonding and activation, the bound geometry has only been resolved at C621. Here, we use molecular dynamics simulations of TRPA1 in both pore-open and pore-closed states to explore the allosteric link between the electrophile binding sites and pore stability. Our simulations reveal that an open pore is structurally stable in the presence of open ‘pockets’ in the C621 / C665 region, but rapidly collapses and closes when these pockets are shut. Binding of electrophiles at either C621 or C665 provides stabilisation of the pore-open state, but molecules bound at C665 are shown to be able to rotate in and out of the pocket, allowing for immediate stabilisation of transient open states. Finally, mutual information analysis of trajectories reveals an informational path linking the electrophile binding site pocket to the pore via the voltage-sensing-like domain, giving a detailed insight into the how the pore is stabilized in the open state.

Download Full-text

Antitumor drugs effect on the stability of double-stranded DNA: steered molecular dynamics analysis

Journal of Biomolecular Structure and Dynamics ◽

10.1080/07391102.2021.1960193 ◽

2021 ◽

pp. 1-10

Author(s):

Rakesh Kumar Mishra ◽

Lakshmi Maganti

Keyword(s):

Molecular Dynamics ◽

Steered Molecular Dynamics ◽

Antitumor Drugs ◽

Dynamics Analysis ◽

Double Stranded Dna ◽

The Stability

Download Full-text

Free energy calculation from steered molecular dynamics simulations using Jarzynski’s equality

The Journal of Chemical Physics ◽

10.1063/1.1590311 ◽

2003 ◽

Vol 119 (6) ◽

pp. 3559-3566 ◽

Cited By ~ 501

Author(s):

Sanghyun Park ◽

Fatemeh Khalili-Araghi ◽

Emad Tajkhorshid ◽

Klaus Schulten

Keyword(s):

Molecular Dynamics ◽

Free Energy ◽

Molecular Dynamics Simulations ◽

Steered Molecular Dynamics ◽

Free Energy Calculation ◽

Energy Calculation ◽

Dynamics Simulations ◽

Jarzynski’S Equality

Download Full-text

Molecular dynamics simulations of mechanical failure in polymorphic arrangements of amyloid fibrils containing structural defects

Beilstein Journal of Nanotechnology ◽

10.3762/bjnano.4.50 ◽

2013 ◽

Vol 4 ◽

pp. 429-440 ◽

Cited By ~ 7

Author(s):

Hlengisizwe Ndlovu ◽

Alison E Ashcroft ◽

Sheena E Radford ◽

Sarah A Harris

Keyword(s):

Mechanical Properties ◽

Molecular Dynamics ◽

Molecular Dynamics Simulations ◽

Amyloid Fibrils ◽

Amyloid Fibril ◽

Steered Molecular Dynamics ◽

Mechanical Failure ◽

Structural Defects ◽

Dynamics Simulations

We examine how the different steric packing arrangements found in amyloid fibril polymorphs can modulate their mechanical properties using steered molecular dynamics simulations. Our calculations demonstrate that for fibrils containing structural defects, their ability to resist force in a particular direction can be dominated by both the number and molecular details of the defects that are present. The simulations thereby suggest a hierarchy of factors that govern the mechanical resilience of fibrils, and illustrate the general principles that must be considered when quantifying the mechanical properties of amyloid fibres containing defects.

Download Full-text