How Molecular Size Impacts RMSD Applications in Molecular Dynamics Simulations

Abstract

The root-mean-square deviation (RMSD) is a similarity measure widely used in analysis of macromolecular structures and dynamics. As increasingly larger macromolecular systems are being studied, dimensionality effects such as the "curse of dimensionality" (a diminishing ability to discriminate pairwise differences between conformations with increasing system size) may exist and significantly impact RMSD-based analyses. For such large bimolecular systems, whether the RMSD or other alternative similarity measures might suffer from this "curse" and lose the ability to discriminate different macromolecular structures had not been explicitly addressed. Here, we show such dimensionality effects for both weighted and nonweighted RMSD schemes. We also provide a mechanism for the emergence of the "curse of dimensionality" for RMSD from the law of large numbers by showing that the conformational distributions from which RMSDs are calculated become increasingly similar as the system size increases. Our findings suggest the use of weighted RMSD schemes for small proteins (less than 200 residues) and nonweighted RMSD for larger proteins when analyzing molecular dynamics trajectories.

The Effect of Recombinant Human Erythropoietin on Bacterial Growth: A Dual-Edged Sword

“…2a–c). However, the RMSD curve is suggestive of high-dimensional data due to the formation of the protein-protein complex [18] (Fig. 2d).…”

The structural and biochemical impacts of monomerizing human acetylcholinesterase

“…MD techniques as well as NMR are potential methods to resolve some of these lingering questions. However, the size of the studied protein can be a major complication in utilizing many of these techniques to the point of being impossible . For instance, NMR is an excellent technique for obtaining dynamic information for different regions and domains of a protein including protein flexibility.…”

“…Additionally, larger macromolecules can affect the root‐mean‐square deviation (RMSD) of structures or atomic coordinates, a measure of similarity that is often used to analyze MD trajectories, modeling, and docking . MD simulations run on larger macromolecules can result in the RMSD losing the ability to discriminate conformation differences between structures and dynamics …”

“…However, the size of the studied protein can be a major complication in utilizing many of these techniques to the point of being impossible. 33 For instance, NMR is an excellent technique for obtaining dynamic information for different regions and domains of a protein including protein flexibility. However, it is generally extremely challenging for proteins exceeding 70 kDa unless the system being studied has unique properties.…”

“…[36][37][38][39] MD simulations run on larger macromolecules can result in the RMSD losing the ability to discriminate conformation differences between structures and dynamics. 33 As the subunit molecular weight of this recombinant hAChE is~60 kDa, dimeric and tetrameric forms of hAChE pose problems for these NMR or MD approaches. The monomerization of hAChE through selective mutagenesis at L380R/F535K appears to offer a new way around these size constraints.…”