Molecular Dynamics Simulation for Levo-Benzedrine to Transmit through Molecular Channels within D&lt;sub&gt;3&lt;/sub&gt;R

Xie, Wei; Xu, Zeren; Wang, Ming; Xu, Shihong

doi:10.3866/pku.whxb201601141

Cited by 5 publications

(7 citation statements)

References 5 publications

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“…The interaction of amino acids used as active sites with small drug molecules directly affects the function of protein. 47 We used the stable DVB-α,β-tubulin-H 2 O system after the dynamics simulation and further energy minimization to study the active site residues. During the energy minimization, the Steep algorithm and PME method was used to calculate the atomic electrostatic interaction.…”

Section: Methodsmentioning

confidence: 99%

“…It is along the vertical direction set as the Z axis direction. SPC H 2 O was added into the box. , To ensure that the system is electrically neutral, sodium ions are used to neutralize the negative charge in the system. Figure shows the structure of DVB-α,β-tubulin-H 2 O system containing 863 residues, a DVB, a GDP, 24 463 H 2 O, and 61 Na + .…”

Section: Methodsmentioning

confidence: 99%

“…The interaction of amino acids used as active sites with small drug molecules directly affects the function of protein . We used the stable DVB-α,β-tubulin-H 2 O system after the dynamics simulation and further energy minimization to study the active site residues.…”

Section: Methodsmentioning

confidence: 99%

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Structural Basis and Mechanism for Vindoline Dimers Interacting with α,β-Tubulin

Zhang

Wang

et al. 2019

ACS Omega

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Vinblastine and its derivatives used in clinics as antitumor drugs often cause drug resistance and some serious side effects; thus, it is necessary to study new vinblastine analogues with strong anticancer cytotoxicity and low toxicity. We designed a dimer molecule using two vindoline-bonded dimer vindoline (DVB) and studied its interaction with α,β-tubulin through the double-sided adhesive mechanism to explore its anticancer cytotoxicity. In our work, DVB was docked into the interface between α-tubulin and β-tubulin to construct a complex protein structure, and then it was simulated for 100 ns using the molecular dynamics technology to become a stable and refined complex protein structure. Based on such a refined structure, the quantum chemistry at the level of the MP2/6-31G(d,p) method was used to calculate the binding energies for DVB interacting with respective residues. By the obtained binding energies, the active site residues for interaction with DVB were found. Up to 20 active sites of residues within α,β-tubulin interacting with DVB are labeled in β-Asp179, β-Glu207, β-Tyr210, β-Asp211, β-Phe214, β-Pro222, β-Tyr224, and β-Leu227 and α-Asn249, α-Arg308, α-Lys326, α-Asn329, α-Ala333, α-Thr334, α-Lys336, α-Lys338, α-Arg339, α-Ser340, α-Thr349, and α-Phe351. The total binding energy between DVB and α,β-tubulin is about −251.0 kJ·mol –1 . The sampling average force potential (PMF) method was further used to study the dissociation free energy (Δ G ) along the separation trajectory of α,β-tubulin under the presence of DVB based on the refined structure of DVB with α,β-tubulin. Because of the presence of DVB within the interface between α- and β-tubulin, Δ G is 252.3 kJ·mol –1 . In contrast to the absence of DVB, the separation of pure β-tubulin needs a free energy of 196.9 kJ·mol –1 . The data show that the presence of DVB adds more 55.4 kJ·mol –1 of Δ G to hinder the normal separation of α,β-tubulin. Compared to vinblastine existing, the free energy required for the separation of α,β-tubulin is 220.5 kJ·mol –1 . Vinblastine and DVB can both be considered through the same double-sided adhesive mechanism to give anticancer cytotoxicity. Because of the presence of DVB, a larger free energy is needed for the separation of α,β-tubulin, which suggests that DVB should have stronger anticancer cytotoxicity than vinblastine and shows that DVB has a broad application prospect.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Structural Basis and Mechanism for Vindoline Dimers Interacting with α,β-Tubulin

Zhang

Wang

et al. 2019

ACS Omega

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“…The principle to calculate the free-energy potential surface is based on the formula G = − RT ln K , where G is free energy and K is the equilibrium constant obtained via molecular simulation. Because similar simulations and calculations have been reported in related articles, ,− we do not introduce the details of simulation but simply provide important points. In this work, we used the system file obtained after the molecular dynamics simulation as the input file of the trajectory dynamics structure system and the topology file necessary for simulating the dynamics trajectories of SBD was the same as it in its simulation of the molecular dynamics structure.…”

Section: Methodsmentioning

confidence: 99%

“…Our results show SBD to have a very unique character preferably moving through a protective channel unlike some molecules preferably moving through the functional channel. 24,25 SBD moves along the functional molecular channel within D 3 R toward the outside of the cell, with a free-energy change of 171.7 kJ·mol –1 , whereas movement toward intracellular orientation induces a free-energy change of 275 kJ·mol –1 . Furthermore, SBD trajectories along the protective molecular channels within D 3 R in the x +, x –, z +, and z – axes toward spaces in the cellular membrane result in free-energy changes of 103.6, 242.1, 459.7, and 127.8 kJ·mol –1 respectively.…”

Section: Introductionmentioning

confidence: 99%

Molecular Mechanism and Dynamics of S-Deoxyephedrine Moving through Molecular Channels within D₃R

Xie

Wang

et al. 2017

ACS Omega

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In this article, the trajectories of S -deoxyephedrine (SBD) along molecular channels within the complex protein structure of third dopamine receptor (D 3 R) are analyzed via molecular dynamic techniques, including potential mean force calculations of umbrella samplings from the 4.5 version of the GROMACS program. Changes in free energy due to the movement of SBD within D 3 R are determined, and the molecular dynamic mechanisms of SBD transmitting along molecular channels are probed. Molecular simulated results show that the change in free energy is calculated as 171.7 kJ·mol –1 for the transmission of SBD toward the outside of the cell along the y + axis functional molecular channel and is 275.0 kJ·mol –1 for movement toward the intracellular structure along the y – axis. Within the internal structure of D 3 R, the changes in free energy are determined to be 103.6, 242.1, 459.7, and 127.8 kJ·mol –1 for transmission of SBD along the x +, x –, z +, and z – axes, respectively, toward the cell bilayer membrane, which indicates that SBD leaves much more easily along the x + axis through the gap between the TM5 (the fifth transmembrane helix) and TM6 (the sixth transmembrane helix) from the internal structure of D 3 R. The values of free-energy changes indicate that SBD molecules can clear the protective channel within D 3 R, which helps dopamine molecules to leave the D 3 R internal structure along the x + axis and to prevent them for exerting excessive neurotransmitter function. Therefore, our results suggest that SBD is effective for development as a drug for treating schizophrenia and its pharmacology is closely related to its dynamics and mechanisms within the molecular pathway of dopamine receptors.

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Disordered linkers in multidomain allosteric proteins: Entropic effect to favor the open state or enhanced local concentration to favor the closed state?

Cao

Lai

et al. 2018

Protein Science

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There are many multidomain allosteric proteins where an allosteric signal at the allosteric domain modifies the activity of the functional domain. Intrinsically disordered regions (linkers) are widely involved in this kind of regulation process, but the essential role they play therein is not well understood. Here, we investigated the effect of linkers in stabilizing the open or the closed states of multidomain proteins using combined thermodynamic deduction and coarse-grained molecular dynamics simulations. We revealed that the influence of linker can be fully characterized by an effective local concentration [B] . When K is smaller than [B] , the closed state would be favored; while the open state would be preferred when K is larger than [B] . We used four protein systems with markedly different domain-domain binding affinity and structural order/disorder as model systems to understand the relationship between [B] and the linker length as well as its flexibility. The linker length is the main practical determinant of [B] . [B] of a flexible linker with 40-60 residues was determined to be in a narrow range of 0.2-0.6 mM, while a too short or too long length would dramatically decrease [B] . With the revealed [B] range, the introduction of a flexible linker makes the regulation of weakly interacting partners possible.

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Molecular Dynamics Simulation for Levo-Benzedrine to Transmit through Molecular Channels within D<sub>3</sub>R

Cited by 5 publications

References 5 publications

Structural Basis and Mechanism for Vindoline Dimers Interacting with α,β-Tubulin

Structural Basis and Mechanism for Vindoline Dimers Interacting with α,β-Tubulin

Molecular Mechanism and Dynamics of S-Deoxyephedrine Moving through Molecular Channels within D₃R

Disordered linkers in multidomain allosteric proteins: Entropic effect to favor the open state or enhanced local concentration to favor the closed state?

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Molecular Dynamics Simulation for Levo-Benzedrine to Transmit through Molecular Channels within D<sub>3</sub>R

Cited by 5 publications

References 5 publications

Structural Basis and Mechanism for Vindoline Dimers Interacting with α,β-Tubulin

Structural Basis and Mechanism for Vindoline Dimers Interacting with α,β-Tubulin

Molecular Mechanism and Dynamics of S-Deoxyephedrine Moving through Molecular Channels within D3R

Disordered linkers in multidomain allosteric proteins: Entropic effect to favor the open state or enhanced local concentration to favor the closed state?

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Molecular Mechanism and Dynamics of S-Deoxyephedrine Moving through Molecular Channels within D₃R