Simulation of non-specific protein-mRNA interactions

Abstract

Protein–nucleic acid interactions exhibit varying degrees of specificity. Relatively high affinity, sequence-specific interactions, can be studied with structure determination, but lower affinity, non-specific interactions are also of biological importance. We report simulations that predict the population of nucleic acid paths around protein surfaces, and give binding constant differences for changes in the protein scaffold. The method is applied to the non-specific component of interactions between eIF4Es and messenger RNAs that are bound tightly at the cap site. Adding a fragment of eIF4G to the system changes both the population of mRNA paths and the protein–mRNA binding affinity, suggesting a potential role for non-specific interactions in modulating translational properties. Generally, the free energy simulation technique could work in harness with characterized tethering points to extend analysis of nucleic acid conformation, and its modulation by protein scaffolds.

Structural Insights into Parasite eIF4E Binding Specificity for m7G and m2,2,7G mRNA Caps

“…Both of these modeled positions on schistosome eIF4E are compatible with our structure and illustrate minimal direct interaction of the RNA with eIF4E. This is consistent with a variety of studies suggesting that eIF4E does not interact specifically with the body of the mRNA (59).…”

Unstructured interactions between peptides and proteins: Exploring the role of sequence motifs in affinity and specificity

“…Most biological processes comprise large, intricate interaction networks which include both specific and nonspecific interactions [1,2] and some of these processes cannot function properly without the participation of nonspecific interactions. For example, nonspecific (unstructured) interactions between proteins (or enzymes) and the nucleic acids are important determinants of biological function [3]. The initial, unstructured interactions of proteins with DNA or RNA can help to facilitate binding to specific sites by reducing the dimensionality of diffusion in DNA replication and DNA modification, by forming distorted binding geometries to activate transcription processes, or even by more indirect regulation of gene expression [4][5][6].…”

RNA–LIM: A novel procedure for analyzing protein/single-stranded RNA propensity data with concomitant estimation of interface structure

“…reduction of both the number of possible ribonucleotide positions on the protein surface and the total number of possible connecting pathways between these positions, with this latter quantity being determined by the calculation of the irregular surface arc between all allowed surface positions [32]. In comparison with molecular dynamics (MD) or Monte Carlo (MC) search-based procedures [12][13][14][15][20][21][22][23][24], the RNA-LIM procedure proffers a number of advantages. Because the RNA-LIM search process is systematic, 8 all of the relevant search space can potentially be enumerated.…”

“…9 A similar limitation is faced when considering very long nucleotide sequences for which N > 6. All three of these disadvantages can be offset by using the RNA-LIM procedure as the first leg of a structure evaluation pipeline to produce coarsegrained candidate structures that can be subsequently used for more detailed analysis using higher order approaches [1][2][3][12][13][14][15][20][21][22][23][24]33]. Despite the less common occurrence of very long segments of ssRNA being involved in binding [1,31], the ssRNA sequence size limitation (N 6 6) could be potentially offset by (i) consideration of longer sequences as a set of smaller sequence fragments or (ii) reconfiguration of the ssRNA homopolymer statistics in terms of every second ribonucleotide.…”

“…However, traditional approaches for elucidating protein double-stranded DNA/ RNA interactions [7][8][9] tend to be less successful when applied to single-stranded RNA (ssRNA) 2 molecules [3,10]. The major reason for this failure is the lack of defined structure associated with flexible ssRNA-a situation that can result in relatively promiscuous, low affinity binding modes [11,12]. The heterogeneous nature of both the ssRNA reactant and the protein-ssRNA complex precludes the use of rigid structure docking methods [7][8][9] and makes all atom molecular dynamics [13] or Monte Carlo [14] search procedures computationally expensive.…”