Abstract
Catalytic loop motions facilitate substrate recognition and binding in many enzymes. While these motions appear to be highly flexible, their functional significance suggests that structure-encoded preferences may play a role in selecting particular mechanisms of motions. We performed an extensive study on a set of enzymes to assess whether the collective/global dynamics, as predicted by elastic network models (ENMs), facilitates or even defines the local motions undergone by functional loops. Our dataset includes a total of 117 crystal structures for ten enzymes of different sizes and oligomerization states. Each enzyme contains a specific functional/catalytic loop (10–21 residues long) that closes over the active site during catalysis. Principal component analysis (PCA) of the available crystal structures (including apo and ligand-bound forms) for each enzyme revealed the dominant conformational changes taking place in these loops upon substrate binding. These experimentally observed loop reconfigurations are shown to be predominantly driven by energetically favored modes of motion intrinsically accessible to the enzyme in the absence of its substrate. The analysis suggests that robust global modes cooperatively defined by the overall enzyme architecture also entail local components that assist in suitable opening/closure of the catalytic loop over the active site.
Highlights
An issue yet to be resolved is the extent to which the intrinsic dynamics of proteins predispose them to ligand binding
As illustrated in the Supporting Information (SI) Figure S1, the experimentally observed closure of loop 6 over the ligand is in accord with the essential/principal mode of motion observed in molecular dynamics (MD) simulations of triosephosphate isomerase (TIM); this first principal mode extracted from MD by essential dynamics analysis (EDA) [14] is in agreement with the global mode predicted for the dimer using the anisotropic network model (ANM) [15,16]
Using a dataset of 117 structures for ten enzymes of different sizes and oligomerization states, we show that the collective modes defined by the protein topology favor loop rearrangements in reasonable agreement with those experimentally observed upon activation
Summary
An issue yet to be resolved is the extent to which the intrinsic dynamics of proteins predispose them to ligand binding. Two different views have been advanced in recent years in linking protein dynamics and function: (i) enzyme structural flexibility affects its catalytic reactivity [1,2,3,4], (ii) catalysis is independent of collective dynamics [5,6,7]. Experiments for TIM indicate that loop closure is not ligand-gated and emerges as an intrinsic motion of the apo enzyme [17]. While these observations signal a role of global dynamics in facilitating functional loop motions, there has been no systematic study of enzyme dynamics in relation to loop motions to establish the generality of these observations, apart from a recent
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