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.

Virtual Simulation System with Path-following Control for Lunar Rovers Moving on Rough Terrain

Virtual simulation technology is of great importance for the teleoperation of lunar rovers during the exploration phase, as well as the design of locomotion systems, performance evaluation, and control strategy verification during the R&D phase. The currently used simulation methods for lunar rovers have several disadvantages such as poor fidelity for wheel-soil interaction mechanics, difficulty in simulating rough terrains, and high complexity making it difficult to realize mobility control in simulation systems. This paper presents an approach for the construction of a virtual simulation system that integrates the features of 3D modeling, wheel-soil interaction mechanics, dynamics analysis, mobility control, and visualization for lunar rovers. Wheel-soil interaction experiments are carried out to test the forces and moments acted on a lunar rover’s wheel by the soil with a vertical load of 80 N and slip ratios of 0, 0.03, 0.05, 0.1, 0.2, 0.3, 0.4, and 0.6. The experimental results are referenced in order to set the parameters’ values for the PAC2002 tire model of the ADAMS/Tire module. In addition, the rough lunar terrain is simulated with 3DS Max software after analyzing its characteristics, and a data-transfer program is developed with Matlab to simulate the 3D reappearance of a lunar environment in ADAMS. The 3D model of a lunar rover is developed by using Pro/E software and is then imported into ADAMS. Finally, a virtual simulation system for lunar rovers is developed. A path-following control strategy based on slip compensation for a six-wheeled lunar rover prototype is researched. The controller is implemented by using Matlab/Simulink to carry out joint simulations with ADAMS. The designed virtual lunar rover could follow the planned path on a rough terrain. This paper can also provide a reference scheme for virtual simulation and performance analysis of rovers moving on rough lunar terrains.

Simulation Environments: Challenges for Advancement

A brief review of the basic terminology on simulation, simulation life-cycle activities such as model-based activities, behavior-oriented activities, and quality assurance activities is given. Then, the challenges and opportunities for the advancement of the state-of-the-art in simulation environments are discussed under the following headings: modelling environments, simulation environments, mixed simulation environments, and comprehensive simulation environments.