A study of collective atomic fluctuations and cooperativity in the U1A–RNA complex based on molecular dynamics simulations

Abstract

Cooperative interactions play an important role in recognition and binding in macromolecular systems. In this study, we find that cross-correlated fluctuations can be used to identify cooperative networks in a protein-RNA system. The dynamics of the RRM-containing protein U1A-stem loop 2 RNA complex have been calculated theoretically from a 10 ns molecular dynamics (MD) simulation. The simulation was analyzed by calculating the covariance matrix of all atomic fluctuations. These matrix elements are then presented in the form of a two-dimensional grid, which displays fluctuations on a per-residue basis. The results indicate the presence of strong, selective cross-correlated fluctuations throughout the RRM in U1A-RNA, which correspond well with the results from a statistical covariance analysis of 330 aligned RRM sequences and previous biophysical studies in which a multiplicity of cooperative networks have been reported. Moreover, the MD results indicate that the various networks identified in separate individual experiments are fluctuationally correlated into a hyper-network encompassing most of the RRM. This method has significant implications as a predictive tool regarding cooperativity in the protein-nucleic acid recognition process.

A study of communication pathways in methionyl- tRNA synthetase by molecular dynamics simulations and structure network analysis

“…The identification of cooperative network of interactions between residues in the protein (U1A)-RNA complex has been carried out by NMR experiments (17,18). More details of communications in this system have been obtained through molecular dynamics (MD) simulations (19,20). This investigation has confirmed that the collective atomic fluctuations obtained from MD simulations agree very well with the experimentally observed cooperativity.…”

“…Two approaches are combined to achieve this goal. First, the dynamically cross-correlated residues in MetRS have been identified from MD simulations by using a method similar to the one used in U1A-RNA complex (19,20). Although this method is powerful in identifying the highly correlated residues involved in the communication path, the correlated residues are not necessarily connected in space; hence, the paths that are spatially connected cannot be detected by this method alone.…”

Characterization of the Dynamics of an Essential Helix in the U1A Protein by Time-Resolved Fluorescence Measurements

“…In addition, a relationship has been implicated between dynamic processes on the pico-to nanosecond time scale and the propagation of the long-range signals required for cooperative interactions. 34,35,[62][63][64] Because conformational changes in C-terminal helices upon complex formation are common in the formation of RRM-RNA complexes, the variation of the dynamics of this region of RRMs may be an important mechanism for gaining affinity or specificity for RNA targets. …”

Intrinsic flexibility of snRNA hairpin loops facilitates protein binding

“…The mechanism of the binding reaction could entail trapping a single loop structure that can be bound by the protein (conformational capture) (Williamson 2000) or making one RNA:protein contact that facilitates subsequent rearrangements of RNA and protein to form the final complex (induced fit) (Frankel and Smith 1998); of course, the reality is likely to be more complicated. Indeed, several possible mechanisms and schemes for U1A binding to SLII have been proposed (Katsamba et al 2001;Pitici et al 2002;Hall 2002, 2004;Kormos et al 2007;Qin et al 2010;1 These authors contributed equally to this work.…”