A molecular dynamics study of the C-terminal fragment of the L7/L12 ribosomal protein

Abstract

The crystallographic dimer of the C-terminal fragment (CTF) of the L7/L12 ribosomal protein has been subjected to molecular dynamics (MD) simulations. A 90 picosecond (ps) trajectory for the protein dimer, 19 water molecules and two counter ions has been calculated at constant temperature. Effects of intermolecular interactions on the structure and dynamics have been studied. The exact crystallographic symmetry is lost and the atomic fluctuations differ from one monomer to the other. The average MD structure is more stable than the X-ray one, as judged by accessible surface area and energy calculations. Crystal (non-dimeric) interactions have been simulated in another 40 ps trajectory by using harmonic restraints to represent intermolecular hydrogen bonds. The conformational changes with respect to the X-ray structure are then virtually suppressed. The unrestrained dimer trajectory has been scanned for cooperative motions involving secondary structure elements. The intrinsic collective motions of the monomer are transmitted via intermolecular contacts to the dimer structure. The existence of a stable dimeric form of CTF, resembling the crystallographic one, has been documented. At the cost of fairly small energy expenditure the dimer has considerable conformational flexibility. This flexibility may endow the dimer with some functional potential as an energy transducer.

MBO(N)D: A multibody method for long-time molecular dynamics simulations

“…Simulations by Åqvist et al, 80,81 using the GRO-MOS force field, found that an important feature of the dynamics of 1CTF is the low frequency motion, around 5 cm −1 , of the B helix relative to the rest of the structure. This motion was clearly displayed when helix C is used as a reference for the relative movement.…”

An estimation method of binding free energy in terms of ABEEMσπ/MM and continuum electrostatics fused into LIE method

“…As Huang et al discussed in their article that the original LIE method based on MD (or Monte Carlo) sampling might be more appropriate than LIE combined with minimization for flexible binding sites, binding site flexibility requires longer MD simulations to reach convergence, which might not be computationally feasible for a large library of compounds in virtual screening. Furthermore, the present approach does not need to add a Born correction term for ionized systems as required in explicit solvent, 26 and the entropic contribution to the binding is taken into account implicitly through the DG tr,rot term and simultaneous consideration of the loss of translational and rotational degrees of freedom on binding. In addition, the present method can be applied to predict the relative binding free energy between the different inhibitors of other target drugs, but similar to the calculation of absolute binding free energy, the parameters of present method are not completely transferable, and therefore, it may be necessary to refit the parameters for applying to other systems.…”

“…24 The linear interaction energy approximation (LIE) is a way of combining molecular mechanics calculations with experimental data to build a model scoring function for the evaluation of ligand-protein binding free energies. LIE method was first suggested by Å qvist and co-workers, [25][26][27][28] which was based on conformational sampling by molecular dynamics (MD) or Monte Carlo trajectory. But in contrast to FEP/TI in which a large number of intermediate windows must be evaluated, the LIE method only requires simulations of the two ending windows.…”

“…26 The linear response approximation provides a physical basis for the treatment of the electrostatic contribution to the binding free energy, which predicts a value of b 5 0.5. 29,30 In fact, the electrostatic scaling factor is also considered a free parameter in the fitting except for a few studies characterized by either a small number of ligands 26,27 or large deviations in some of the predicted binding energies. 31,32 The LIE method was already applied to many areas in the calculation of binding free energy with an accurate result.…”

Critical evaluation of the research docking program for the CASP2 challenge

“…This has the effect of limiting longrange electrostatic interactions without compromising short-range hydrogen bonds. 9 Intramolecular interactions are represented by van der Waals and torsional terms. In cases where the intramolecular energy is not used, conformations are checked for steric clash by comparing distances between atoms in the ligand, and rejecting a trial state in the Monte Carlo procedure if a clash is detected.…”