RNA bulge entropies in the unbound state correlate with peptide binding strengths for HIV-1 and BIV TAR RNA because of improved conformational access

Abstract

For the binding of peptides to wild-type HIV-1 and BIV TAR RNA and to mutants with bulges of various sizes, changes in the DeltaDelta G values of binding were determined from experimental K d values. The corresponding entropies of these bulges are estimated by enumerating all possible RNA bulge conformations on a lattice and then applying the Boltzmann relationship. Independent calculations of entropies from fluctuations are also carried out using the Gaussian network model (GNM) recently introduced for analyzing folded structures. Strong correlations are seen between the changes in free energy determined for binding and the two different unbound entropy calculations. The fact that the calculated entropy increase with larger bulge size is correlated with the enhanced experimental binding free energy is unusual. This system exhibits a dependence on the entropy of the unbound form that is opposite to usual binding models. Instead of a large initial entropy being unfavorable since it would be reduced upon binding, here the larger entropies actually favor binding. Several interpretations are possible: (i) the higher conformational freedom implies a higher competence for binding with a minimal strain, by suitable selection amongst the set of already accessible conformations; (ii) larger bulge entropies enhance the probability of the specific favorable conformation of the bound state; (iii) the increased freedom of the larger bulges contri-butes more to the bound state than to the unbound state; (iv) indirectly the large entropy of the bound state might have an unfavorable effect on the solvent structure. Nonetheless, this unusual effect is interesting.

Chemistry and Biochemistry of 2, 5-Oligoadenylate-Based Antisense Strategy

“…The other two stands are of varying lengths, allowing different lengths for A-form helical stem II A stable local structure consisting just of a single base pair is unlikely. Similar lattice methods have shown success in characterizing RNA flexibilities and their related entropies [30]. 3), including two non-canonical pairs A9-G12, G8-A13 adjacent to G10.1-C11.1 and U7-A14 [24].…”

A Physical Origin for Functional Domain Structure in Nucleic Acids as Evidenced by Cross-linking Entropy: I

“…However, we have applied these concepts from a di!erent perspective than what is brought out in the literature, including works devoted to the biosciences. This work bears some resemblance to earlier work in loop weighting functions (Sche%er et al, 1970) and also parallels a recently developed methodology in protein structure calculations known as the Gaussian polymer network (GPN) model (Lustig et al, 1998;Keskin et al, 2000;Debe & Goddard, 1999). In addition, Frederic et al, 1996) have also developed a related approach on 3-D structures for the ends of the sequence.…”

“…In principle, the loop weight function approach could be modi"ed by adopting the weight relations derived in eqn (9), where the degree of cooperativity is incorporated into the problem via the persistence length (the &&link''). The Gaussian polymer network model (Keskin et al, 2000;Lustig et al, 1998;Debe & Goddard, 1999) also uses linear weights but could be modi-"ed accordingly to show this e!ect.…”

Molecular recognition of RNA: challenges for modelling interactions and plasticity

“…Hence, GNM allows deriving information where conformational changes will be most pronounced. Furthermore, fluctuations calculated by GNM have already been shown to be useful for estimating entropic contributions to the change of free energy for the bulge regions of the Bovine Immunodeficiency Virus (BIV) and HIV-1 TAR-RNA structures (Lustig et al, 1998). These results are encouraging in view of applications in SBDD approaches.…”