scholarly journals Dynamical control by water at a molecular level in protein dimer association and dissociation

2020 ◽  
Vol 117 (5) ◽  
pp. 2302-2308 ◽  
Author(s):  
Puja Banerjee ◽  
Biman Bagchi
Keyword(s):  
Free Energy ◽  
Transition State ◽  
Large Scale ◽  
Hydrophobic Hydration ◽  
Active Role ◽  
Separation Distance ◽  
Density Fluctuations ◽  
Dynamics Simulation ◽  
Free Energy Surface ◽  
Protein Dissociation

Water, often termed as the “lubricant of life,” is expected to play an active role in navigating protein dissociation–association reactions. In order to unearth the molecular details, we first compute the free-energy surface (FES) of insulin dimer dissociation employing metadynamics simulation, and then carry out analyses of insulin dimerization and dissociation using atomistic molecular-dynamics simulation in explicit water. We select two sets of initial configurations from 1) the dissociated state and 2) the transition state, and follow time evolution using several long trajectories (∼1–2 μs). During the process we not only monitor configuration of protein monomers, but also the properties of water. Although the equilibrium structural properties of water between the two monomers approach bulklike characteristics at a separation distance of ∼5 nm, the dynamics differ considerably. The complex association process is observed to be accompanied by several structural and dynamical changes of the system, such as large-scale correlated water density fluctuations, coupled conformational fluctuation of protein monomers, a dewettinglike transition with the change of intermonomeric distance RMM from ∼4 to ∼2 nm, orientation of monomers and hydrophobic hydration in the monomers. A quasistable, solvent-shared, protein monomer pair (SSPMP) forms at around 2 nm during association process which is a local free-energy minimum having ∼50–60% of native contacts. Simulations starting with arrangements sampled from the transition state (TS) of the dimer dissociation reveal that the final outcome depends on relative orientation of the backbone in the “hotspot” region.

scholarly journals An Asymmetric Mechanism in a Symmetric Molecular Machine

2020 ◽  
Author(s):  
Florian Blanc ◽  
Marco Cecchini
Keyword(s):  
Free Energy ◽  
Large Scale ◽  
Technological Development ◽  
Thermal Fluctuations ◽  
Free Energy Calculations ◽  
Molecular Machine ◽  
Free Energy Surface ◽  
Promising Area ◽  
Sequential Mechanism ◽  
External Stimuli

The design of molecular architectures exhibiting functional motions is a promising area for disruptive technological development. Towards this goal, rotaxanes and catenanes, which undergo relative motions of their sub-units in response to external stimuli, are prime candidates. Here, we report on the computational analysis of the contraction/extension of a bistable [c2]-daisy chain rotaxane. Using free energy calculations and transition path optimizations, we explore the free energy landscape governing the functional motions of a prototypical molecular machine with atomic resolution.<br>The calculations reveal a sequential mechanism for contraction/extension in which the asynchronous gliding of each ring is preferred over the concerted movement suggested by chemical intuition. Analysis of the underlying free energy surface indicates that dissymmetric gliding is favored because it entails crossings of much smaller barriers.<br>Our findings illustrate an important design principle for molecular machines, namely that efficient exploitation of thermal fluctuations may be realized by breaking down the large-scale functional motions into smaller steps.

Li deposition and desolvation with electron transfer at a silicon/propylene-carbonate interface: transition-state and free-energy profiles by large-scale first-principles molecular dynamics

2018 ◽  
Vol 20 (17) ◽  
pp. 11586-11591 ◽  
Author(s):  
Tsukuru Ohwaki ◽  
Taisuke Ozaki ◽  
Yukihiro Okuno ◽  
Tamio Ikeshoji ◽  
Hideto Imai ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Free Energy ◽  
First Principles ◽  
Large Scale ◽  
Dynamics Simulation ◽  
Charge Transfer Process ◽  
Energy Profiles ◽  
Process Coupling ◽  
Free Energy Profiles ◽  
First Principles Molecular Dynamics

We report the result of a large-scale first-principles molecular dynamics simulation under different electric biases performed to understand the charge transfer process coupling with lithium deposition and desolvation processes.

scholarly journals Sampling the Folding Transition State Ensemble in a Tube-Like Model of Protein

10.29007/ml3c ◽  
2020 ◽  
Author(s):  
Ba Hung Nguyen ◽  
Hoang Trinh Xuan
Keyword(s):  
Free Energy ◽  
Transition State ◽  
Energy Surface ◽  
Sampling Technique ◽  
Small Region ◽  
Umbrella Sampling ◽  
Free Energy Surface ◽  
State Ensemble ◽  
State Region ◽  
Transition State Ensemble

We used the tube model with Go-like potential for native contacts to study the folding transition of a designed three-helix bundle and a designed protein G-like structure. It is shown that both proteins in this model are two-state folders with a cooperative folding transition coincided with the collapse transition. We defined the transition states as protein conformations in a small region around the saddle point on a free energy surface with the energy and the conformational root-mean-square deviation (RMSD) from the native state as the coordinates. The transition state region on the free energy surface then was sampled by using the umbrella sampling technique. We show that the transition state ensemble is broad consisting of different conformations that have different folded and unfolded elements.

scholarly journals Probing the importance of hydrogen bonds in the active site of the subtilisin nattokinase by site-directed mutagenesis and molecular dynamics simulation

2006 ◽  
Vol 395 (3) ◽  
pp. 509-515 ◽  
Author(s):  
Zhong-liang Zheng ◽  
Mao-qing Ye ◽  
Zhen-yu Zuo ◽  
Zhi-gang Liu ◽  
Keng-chang Tai ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Free Energy ◽  
Hydrogen Bonds ◽  
Transition State ◽  
Enzyme Kinetics ◽  
Structural Model ◽  
Catalytic Triad ◽  
Site Directed Mutagenesis ◽  
Dynamics Simulation ◽  
Directed Mutagenesis

Hydrogen bonds occurring in the catalytic triad (Asp32, His64 and Ser221) and the oxyanion hole (Asn155) are very important to the catalysis of peptide bond hydrolysis by serine proteases. For the subtilisin NK (nattokinase), a bacterial serine protease, construction and analysis of a three-dimensional structural model suggested that several hydrogen bonds formed by four residues function to stabilize the transition state of the hydrolysis reaction. These four residues are Ser33, Asp60, Ser62 and Thr220. In order to remove the effect of these hydrogen bonds, four mutants (Ser33→Ala33, Asp60→Ala60, Ser62→Ala62, and Thr220→Ala220) were constructed by site-directed mutagenesis. The results of enzyme kinetics indicated that removal of these hydrogen bonds increases the free-energy of the transition state (ΔΔGT). We concluded that these hydrogen bonds are more important for catalysis than for binding the substrate, because removal of these bonds mainly affects the kcat but not the Km values. A substrate, SUB1 (succinyl-Ala-Ala-Pro-Phe-p-nitroanilide), was used during enzyme kinetics experiments. In the present study we have also shown the results of FEP (free-energy perturbation) calculations with regard to the binding and catalysis reactions for these mutant subtilisins. The calculated difference in FEP also suggested that these four residues are more important for catalysis than binding of the substrate, and the simulated values compared well with the experimental values from enzyme kinetics. The results of MD (molecular dynamics) simulations further demonstrated that removal of these hydrogen bonds partially releases Asp32, His64 and Asn155 so that the stability of the transition state decreases. Another substrate, SUB2 (H-D-Val-Leu-Lys-p-nitroanilide), was used for FEP calculations and MD simulations.

scholarly journals An Asymmetric Mechanism in a Symmetric Molecular Machine

2020 ◽  
Author(s):  
Florian Blanc ◽  
Marco Cecchini
Keyword(s):  
Free Energy ◽  
Large Scale ◽  
Technological Development ◽  
Thermal Fluctuations ◽  
Free Energy Calculations ◽  
Molecular Machine ◽  
Free Energy Surface ◽  
Promising Area ◽  
Sequential Mechanism ◽  
External Stimuli

The design of molecular architectures exhibiting functional motions is a promising area for disruptive technological development. Towards this goal, rotaxanes and catenanes, which undergo relative motions of their sub-units in response to external stimuli, are prime candidates. Here, we report on the computational analysis of the contraction/extension of a bistable [c2]-daisy chain rotaxane. Using free energy calculations and transition path optimizations, we explore the free energy landscape governing the functional motions of a prototypical molecular machine with atomic resolution.<br>The calculations reveal a sequential mechanism for contraction/extension in which the asynchronous gliding of each ring is preferred over the concerted movement suggested by chemical intuition. Analysis of the underlying free energy surface indicates that dissymmetric gliding is favored because it entails crossings of much smaller barriers.<br>Our findings illustrate an important design principle for molecular machines, namely that efficient exploitation of thermal fluctuations may be realized by breaking down the large-scale functional motions into smaller steps.

scholarly journals Sampling the Folding Transition State Ensemble in a Tube-like Model of Protein

2019 ◽  
Vol 29 (2) ◽  
pp. 129
Author(s):  
Nguyen Ba Hung ◽  
Trinh Xuan Hoang
Keyword(s):  
Free Energy ◽  
Transition State ◽  
Energy Surface ◽  
Sampling Technique ◽  
Small Region ◽  
Umbrella Sampling ◽  
Free Energy Surface ◽  
State Ensemble ◽  
State Region ◽  
Transition State Ensemble

We used the tube model with Go-like potential for native contacts to study the folding transition of a designed three-helix bundle and a designed protein G-like structure. It is shown that both proteins in this model are two-state folders with a cooperative folding transition coincided with the collapse transition. We defined the transition states as protein conformations in a small region around the saddle point on a free energy surface with the energy and the conformationalroot mean square deviation (rmsd) from the native state as the coordinates. The transition state region on the free energy surface then was sampled by using umbrella sampling technique. We show that the transition state ensemble is broad consisting of different conformations that have different folded and unfolded elements.

Optimizing the Structures of Minimum and Transition State on the Free Energy Surface

2005 ◽  
Vol 109 (1) ◽  
pp. 197-204 ◽  
Author(s):  
Sheng-Yong Yang ◽  
Iordan Hristov ◽  
Paul Fleurat-Lessard ◽  
Tom Ziegler
Keyword(s):  
Free Energy ◽  
Transition State ◽  
Energy Surface ◽  
Free Energy Surface
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