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this manuscript, we introduce the Cumulative Variance of Coordinate
Fluctuations (CVCF) along atomistic MD trajectories, as a dynamical metric to
examine protein dynamics and sampling convergence in MD simulations. Using model 1D and 2D PES, we first show that
CVCF, which traces over the fluctuations of protein atoms as a function of
sampling coordinate (time in MD simulations), captures both local and global
equilibria to distinguish the underlying PES of proteins. For both model PES and protein trajectories,
we compare the information content present in CVCF traces with that obtained
using other measures proposed in literature to reveal conditions under which a
consistent interpretation of data can be obtained. Importantly, we show that
independent of convergence to either local or global equilibrium, the values
and features of protein CVCF can provide a comparative assessment of the
ruggedness and curvature of the underlying PES sampled by proteins along MD
trajectories. Trends in CVCF therefore enable us to compare features of the
PES across multiple protein systems using MD simulations. We demonstrate some
of the attractive features of a CVCF based analysis on multi-microsecond (ms) MD trajectories of structurally homologous
ubiquitin family proteins which present a particularly striking example in
nature wherein sequence changes and complexation which do not lead to prominent
structural changes bring about dramatic functional consequences.