Exploring unbinding mechanism of drugs from SERT via molecular dynamics simulation and its implication in antidepressants

The human serotonin transporter(SERT)terminates neurotransmission by removing serotonin from the synaptic cleft,which is an essential process that plays an important role in depression.In addition to natural substrate serotonin,SERT is also the target of the abused drug cocaine and,clinically used antidepressants,escitalopram,and paroxetine.To date,few studies have attempted to investigate the unbinding mechanism underlying the orthosteric and allosteric modulation of SERT.In this article,the conserved property of the orthosteric and allosteric sites(S1 and S2)of SERT was revealed by combining the high resolutions of x-ray crystal structures and molecular dynamics(MD)simulations.The residues Tyr95 and Ser438 located within the S1 site,and Arg104 located within the S2 site in SERT illustrate conserved interactions(hydrogen bonds and hydrophobic interactions),as responses to selective serotonin reuptake inhibitors.Van der Waals interactions were keys to designing effective drugs inhibiting SERT and further,electrostatic interactions highlighted escitalopram as a potent antidepressant.We found that cocaine,escitalopram,and paroxetine,whether the S1 site or the S2 site,were more competitive.According to this potential of mean force(PMF)simulations,the new insights reveal the principles of competitive inhibitors that lengths of trails from central SERT to an opening were~18A for serotonin and~22 A for the above-mentioned three drugs.Furthermore,the distance between the natural substrate serotonin and cocaine(or escitalopram)at the allosteric site was~3A.Thus,it can be inferred that the potent antidepressants tended to bind at deeper positions of the S1 or the S2 site of SERT in comparison to the substrate.Continuing exploring the processes of unbinding four ligands against the two target pockets of SERT,this study observed a broad pathway in which serotonin,cocaine,escitalopram(at the S1 site),and paroxetine all were pulled out to an opening between MT1b and MT6a,which may be helpful to understand the dissociation mechanism of antidepressants.

Prediction of aqueous solubility of PCBs based on molecular structure

The thermodynamic relationships among aqueous solubility and molar volume (MV) , total molecular surface area (TSA) and molecular connectivity index (MCI) for highly hydrophobic chemicals. PCBs are established and discussed, respectively. Good linear relationships exist among In Cs and MV, TSA or MCI.

Rupintrivir is a promising candidate for treating severe cases of Enterovirus-71 infection

AIM:To evaluate the suitability of rupintrivir against Enterovirus 71(EV71)induced severe clinical symptoms using computational methods. METHODS:The structure of EV71 3C protease was predicted by homology modeling.The binding free energies between rupintrivir and EV71 3C and human rhinovirus 3C protease were computed by molecular dynamics and molecular mechanics Poisson-Boltzmann/ surface area and molecular mechanics generalized-born/ surface area methods.EV71 3C fragments obtained from clinical samples collected during May to July 2008 in Shanghai were amplified by reverse-transcription and polymerase chain reaction and sequenced. RESULTS:We observed that rupintrivir had favorable binding affinity with EV71 3C protease(-10.76 kcal/mol). The variability of the 3C protein sequence in isolates of various outbreaks,including those obtained in our hospital from May to July 2008,were also analyzed to validate the conservation of the drug binding pocket. CONCLUSION:Rupintrivir,whose safety profiles had been proved,is an attractive candidate and can be quickly utilized for treating severe EV71 infection.

Evaluation on performance of MM/PBSA in nucleic acid-protein systems

The molecular mechanics/Poisson-Boltzmann surface area(MM/PBSA) method has been widely used in predicting the binding affinity among ligands,proteins,and nucleic acids.However,the accuracy of the predicted binding energy by the standard MM/PBSA is not always good,especially in highly charged systems.In this work,we take the protein-nucleic acid complexes as an example,and showed that the use of screening electrostatic energy(instead of Coulomb electrostatic energy) in molecular mechanics can greatly improve the performance of MM/PBSA.In particular,the Pearson correlation coefficient of dataset Ⅱ in the modified MM/PBSA(i.e.,screening MM/PBSA) is about 0.52,much better than that(<0.33)in the standard MM/PBSA.Further,we also evaluate the effect of solute dielectric constant and salt concentration on the performance of the screening MM/PBSA.The present study highlights the potential power of the screening MM/PBSA for predicting the binding energy in highly charged bio-systems.

Molecular Dynamics Simulations and Steered Molecular Dynamics Simulations of Glabridin Bound to Wild Type and V30A Mutant Transthyretin： Ligand-linked Perturbation of Tertiary Conformation

Transthyretin（TTR）, as a tetrameric protein, functions as a neuroprotector. The native TTR homotetramer dissociates into dimers and monomers. Dimers and monomers self-assemble into amyloid fibrils, and this process can lead to some diseases. Native TTR homotetramer is a widely accepted model for TTR amyloid formation. In this study, simulations using molecular dynamics（MD） and steered MD（SMD） were performed to explore the mechanisms for glabridin（Glab）, a specific inhibitor for TTR binding, for V30A mutant and wild-type（WT） TTR. MD simulation results indicate that, compared with Glab binding to WT and V30A mutant, the WT TTR could lead to the collapse of β-strands from Ser52 to His56 at chain A. This phenomenon facilitated the easy dissociation of chains A and C. Calculations of the binding free energy between the two chains showed that the V30A-Glab TTR complex displayed a lower binding energy than other systems（WT TTR and WT-Glab TTR）. Then, SMD simulation was performed to ex- plore the unbinding pathway for Glab through the WT and V30A mutant TTR. The results show that Lysl 5（chain A） produced a hydrogen bond with Glab at the force peak via the WT TTR tunnel. Meanwhile, in the V30A TTR mutant, the hydrogen bond between Lysl 5（chain A） and Glab was broken at the force peak. This condition was beneficial for Glab to be taken off from the protein. Our theoretical results will be useful in designing a new specific inhibitor of TTR protein to control the TTR homotetramer dissociation.

New Investigation of Potential Acting on an Electron in a Molecule to Draw Molecular Faces

A new approach to calculate the potential acting on an electron in a molecule（PAEM） has been established for drawing the molecular face（MF） of a macromolecule, according to the classic point charge model and the atom-bond electronegativity equalization method（ABEEMσπ） for one electron in a molecule. We introduced a dy- namic charge distribution from the view of a local electron movement in a molecule based on the new approach, and as further direct evidence, we calculated some physical quantities using the original ab initio method and the new method to verify the accuracy of the method, such as the boundary distance（BD）, molecular face surface area（MFSA） and molecular reactivities indicated by the MFs for a variety of organic molecules. All the results by the new method are in agreement with the results by ab initio method.