Structure and stability of RNA/RNA kissing complex: with application to HIV dimerization initiation signal

Abstract

We develop a statistical mechanical model to predict the structure and folding stability of the RNA/RNA kissing-loop complex. One of the key ingredients of the theory is the conformational entropy for the RNA/RNA kissing complex. We employ the recently developed virtual bond-based RNA folding model (Vfold model) to evaluate the entropy parameters for the different types of kissing loops. A benchmark test against experiments suggests that the entropy calculation is reliable. As an application of the model, we apply the model to investigate the structure and folding thermodynamics for the kissing complex of the HIV-1 dimerization initiation signal. With the physics-based energetic parameters, we compute the free energy landscape for the HIV-1 dimer. From the energy landscape, we identify two minimal free energy structures, which correspond to the kissing-loop dimer and the extended-duplex dimer, respectively. The results support the two-step dimerization process for the HIV-1 replication cycle. Furthermore, based on the Vfold model and energy minimization, the theory can predict the native structure as well as the local minima in the free energy landscape. The root-mean-square deviations (RMSDs) for the predicted kissing-loop dimer and extended-duplex dimer are~3.0 Å . The method developed here provides a new method to study the RNA/RNA kissing complex.

Predicting structure and stability for RNA complexes with intermolecular loop–loop base-pairing

“…In addition, the stable structure of the SL1/SL1 complex is a linear dimer, which is different from the kissing complex determined by previous NMR measurement for the truncated short SL1 sequence (Laughrea and Jette 1994;Muriaux et al 1996;Ennifar et al 2001;Paillart et al 2004;Ulyanov et al 2006). Our previous theoretical study (Cao and Chen 2011) on the truncated SL1 sequence also showed that the linear dimer and the kissing complex coexist at room temperature. However, the previous model cannot be used to predict the complex structure of the whole SL1 domain.…”

“…We note that hairpin loop kissing complexes often favor the formation of coaxial stacking interactions. The entropy parameters for the hairpin kissing complexes listed in Table 1 of the article by Cao and Chen (2011) are for hairpin kissing systems with three helices coaxially stacked.…”

“…The previously developed model (Cao and Chen 2011) can only treat simple kissing interaction between hairpin loops. For large, more complex structures of long RNA sequences, the previous method is not useful due to (1) lack of entropy parameters for more complex loop-loop contacts (such as the kissing interactions between two internal loops or multibranched junctions) and (2) the huge conformational sampling space for large structures.…”

“…Recently, we used the Vfold model to calculate the entropy parameters and predict the structure and stability of the simple kissing interaction between two hairpin loops (Cao and Chen 2011). Tests against experimental data suggest that the entropy parameters for the formation of the kissing interaction may be reliable.…”

“…A main advancement in the current new model is a method for estimating the entropy parameters (Cao and Chen 2011) for structures with general loop-loop base-pairing. The model enables us to predict the structure and folding thermodynamics of complicated RNA/RNA complexes.…”