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Targeted Molecular Dynamics (TMD) Simulation


Molecular dynamics (MD) simulations have proven to be a powerful tool for investigating the dynamic behavior of stable macromolecules at finite temperatures. However, a diversity of conformational transitions can take place during a simulation. The path and mechanism of conformational activation are of vital importance in understanding its biological functions. The conformational change outlined here is very large and complex, and unlikely to happen in an ordinary molecular dynamics simulation. Targeted molecular dynamics is a technique developed based on MD simulation and is able to simulate more elaborate conformational changes in proteins.

Principles of TMD Simulation

The TMD method establishes a distance constraint between two structures, such that the sum over the distances of all atoms between the initial and the target structure has to be reduced in every step of the simulation. It induces a conformational change to a known target structure at ordinary temperature by applying a time-dependent, purely geometrical constraint. The transition is enforced independently of the height of energy barriers, while the dynamics of the molecule is only minimally influenced by the constraint.

An overview of the positions chosen for the TMD procedure.Figure 1. An overview of the positions chosen for the TMD procedure. EtBr is depicted as red CPK models and NUNL02 as yellow CPK models while the AcrB protein is displayed as a blue ribbon structure. (Lande, S. J.; et al. 2018)

Application of TMD Simulation

  • Model the pathways
  • Conformational transition simulation
  • Explore ligand binding reaction coordinates

Our TMD Simulation Process

Since the TMD method creates a distance constraint between two structures, and the two structures are required to conduct a simulation, for example, an initial and a final structure. The only information necessary to perform TMD calculations are detailed three-dimensional structures for the complex in both an initial and a final, or target, state.

  • We first use the pathway from the initial to the final structure to describe the direction the simulation takes.
  • In each step of the simulation, our teams perform an unconstrained step of a MD simulation.
  • After the free simulation step, we reduce the distance between the initial and target structure by using the distance constraints ρ which is defined as the sum of distances of all atom positions.

Our Services

  • Investigate the configurational space for pathways

We use TMD simulation to explore the configurational space for pathways accessible at a given temperature. The transitions we study include unfolding of an α-helical portion and, in the reverse direction, refolding from an extended conformation. In addition, we are capable of performing the search for energy barriers and stable intermediates from rather local changes up to protein denaturation using TMD method.

  • Study the cell activation process

Our experts apply TMD simulation to investigate the cell activation process and reveal its internal mechanism. We study the complete process of changing from the inactive state to the active state. Moreover, we can explore each stage of the TMD trajectory such as non-activated, transitional state, and activated state combined with our knowledge on cluster analysis.

  • Study the cytoplasmic domain

We mainly use TMD simulation to investigate the residues in the cytoplasmic domain and their interactions.

  • Simulation of conformational transitions

1. Alfa Chemistry has developed a restricted perturbation-targeted molecular dynamics method for the simulation of conformational transitions. Our restricted perturbation-TMD simulation method limits the conformational change at each molecular dynamics step to a fixed size, minimizing the root mean square deviation from the target. The method has proven to be more efficient and able to yield lower energy pathways.

2. We perform TMD on the simulation of a large conformational transition, in which the intermediate is only used as a first guess, and TMD enables a refinement of the intermediate structures on the pathway.

  • Study the protein-ligand unbinding

We apply the dissipation-corrected targeted molecular dynamics simulations for the prediction of pathways, rates and rate-limiting steps in protein-ligand unbinding. The coarse-grained dynamics along the reaction coordinate and mechanisms of the whole process is able to be learned either.

Our Advantages

  • Alfa Chemistry supports different TMD simulation approaches such as a restricted perturbation-targeted molecular dynamics method and dissipation-corrected targeted molecular dynamics simulations.
  • Our additional extension for the TMD algorithm assists in the performance of TMD simulation.
  • We are capable of combing several methods. Our scientists can perform TMD simulations to calculate the conformational change between two structures, and use standard MD simulations to relax the structures of the active, the intermediate and the latent molecule and the rigid body rotation to obtain a first guess for the intermediate.

Our targeted molecular dynamics (TMD) simulation services remarkably reduce the cost, promote further experiments, and accelerate the process of drug design for customers worldwide. Our personalized and all-around services will satisfy your innovative study demands. If you are interested in our services, please don't hesitate to contact us. We are glad to cooperate with you and witness your success!


  • Lande, S. J.; et al. Targeted Molecular Dynamics Simulations Suggest Direct Ligand Competition as a Plausible Efflux Inhibition Mechanism in the Multidrug Resistance Pump AcrB. bioRxiv. 2018.

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