Locally accessible conformations of proteins: Multiple molecular dynamics simulations of crambin

Abstract

Multiple molecular dynamics (MD) simulations of crambin with different initial atomic velocities are used to sample conformations in the vicinity of the native structure. Individual trajectories of length up to 5 ns sample only a fraction of the conformational distribution generated by ten independent 120 ps trajectories at 300 K. The backbone atom conformational space distribution is analyzed using principal components analysis (PCA). Four different major conformational regions are found. In general, a trajectory samples only one region and few transitions between the regions are observed. Consequently, the averages of structural and dynamic properties over the ten trajectories differ significantly from those obtained from individual trajectories. The nature of the conformational sampling has important consequences for the utilization of MD simulations for a wide range of problems, such as comparisons with X-ray or NMR data. The overall average structure is significantly closer to the X-ray structure than any of the individual trajectory average structures. The high frequency (less than 10 ps) atomic fluctuations from the ten trajectories tend to be similar, but the lower frequency (100 ps) motions are different. To improve conformational sampling in molecular dynamics simulations of proteins, as in nucleic acids, multiple trajectories with different initial conditions should be used rather than a single long trajectory.

Dynamics and unfolding pathways of a hyperthermophilic and a mesophilic rubredoxin

“…New hydrogen bonds formed after molecular dynamics at 300 K (Phillips, 1990), which are expected to be particularly important for a small protein, and, in part, to errors in the analysis of the X-ray data (Kuriyan et al, 1986 Principal components analysis of the trajectories was performed (Caves et al, 1998) and the projections of the trajectories onto the first two principal components (PCl, PC2) is shown in Figure 6. The first two principal components (lowest frequencies) account for 50-55% of the total RMS displacement.…”

Algorithmic dimensionality reduction for molecular structure analysis

“…By lowering the number of effective degrees of freedom, more meaningful visualizations might be obtained and undesirable effects from the so-called "curse of dimensionality" can be removed. 32 In addition to filtering high-frequency motions, dimensionality reduction of molecular simulations can be utilized to identify discrete conformational substates 24,33,34 and for understanding the extent of configuration space sampling and the topography of the system's energy hypersurface. 35 As reviewed by Altis et al, 36 dimensionality reduction can be utilized to obtain representations for reaction coordinates and free energy landscapes as well as the transition matrix between metastable conformational states.…”

Computed Energetics of Nucleotides in Spatial Ribozyme Structures: An Accurate Identification of Functional Regions from Structure

“…The reasons for combining the UFF and AMBER force fields are also mentioned in Appendix I. These calculations were performed using a "multiple trajectories" technique [26,27] that is more likely to produce models closer to experimental structures than simply an energy minimization or a singular long trajectory of molecular dynamics. Apart from NMR and crystal structures of ribozymes [1,6,7,8,9,10,11,12,13,28,29,30,31,32], the method was also applied to RNAs of other types [33,34,35] as well as to several structural models of ribozymes [36,37,38].…”

“…The calculations used "swarm" or "multiple trajectory" technique [26,27]. Calculations were made without hetero-atoms using either explicit or implicit modelling of solvent.…”

“…For example, calculation of the energy histogram for hammerhead ribozymes (PDB 1hmh), even using the multiple trajectories technique [26,27,58] (as in the script below) takes only 45 sec on a 3Ghz PC computer (using implicit solvent modeling). The procedural "script" or "macro", designed for the purposes of the present study, is shown below.…”