Targeted Molecular Dynamics (TMD) Simulation

Targeted Molecular Dynamics (TMD) is a method that induces conformational changes in a structure based solely on constraints applied to minimize the root mean square deviation between initial and final (target) structures. TMD has been used previously to examine protein conformational changes induced by ligand binding and to explore ligand binding reaction coordinates. The only information necessary to perform TMD calculations are detailed three-dimensional structures for the complex in both an initial (I) and a final (F), or target, state. The I and F states are usually obtained from x-ray diffraction or NMR studies for the ligand-protein complex.

Figure 1. TMD simulation.

Principle

In TMD, subset of atoms in the simulation is guided towards a final 'target' structure by means of steering forces. At each timestep, the RMS distance between the current coordinates and the target structure is computed (after first aligning the target structure to the current coordinates). The force on each atom is given by the gradient of the potential.

U_TMD=1/2*k/N[RMS(t)-RMS^*(t)]²

Where RMS is the instantaneous best-fit RMS distance of the current coordinates from the target coordinates, and RMS evolves linearly from the initial RMSD at the first TMD step to the final RMSD at the last TMD step. Atoms can be separated into non-overlapping constraint domains by assigning integer values in the beta column of the TMDFile. Forces on the atoms will be calculated for each domain independently of the other domains.Within each domain, the set of atoms used to fit the target structure can be different from the set of atoms that are biased towards the target structure.

Overall solutions

CD ComputaBio can provide you with professional TMD services and result analysis services. The CHARMM force field was used with a united-atom description of the protein. The solvent was taken into account through an implicit model because it would be computationally prohibitive to perform many unfolding simulations with explicit water molecules. Moreover, the implicit model provides a mean field description of the solvent which avoids the problems related to the relaxation of explicit water molecules around the protein. This is particularly important for both TMD and unfolding athigh temperature, since the conformational change is strongly accelerated and explicit solvent would show significantly increased friction.

Our Features

• In TMD, the force field is supplemented with harmonic constraints that promote an increase in the conformational distance from the original state or a decrease in the distance from the target unfolded structure.
• As a basis for comparison, the unfolding process can be simulated by conventional (ie unconstrained) molecular dynamics at 375 and 475 K.
• In all simulations, the solvated implicit approximate adiabatic is used to simulate the solvent response, which is suitable for the simulation method used here for nanosecond expansion. The CI2 simulation performed by the dosing model showed a similar sequence of events. If you have any needs in this regard, please feel free to contact us.