Assessing the Quality of in Silico Produced Biomolecules: The Discovery of a New Conformer

Abstract

The computational procedures for predicting the 3D structure of aptamers interacting with different biological molecules have gained increasing attention in recent years. The information acquired through these methods represents a crucial input for research, especially when relevant crystallographic data are not available. A number of software programs able to perform macromolecular docking are currently accessible, leading to the prediction of the quaternary structure of complexes formed by two or more interacting biological macromolecules. Nevertheless, the scoring protocols employed for ranking the candidate structures do not always produce satisfactory results, making difficult the identification of structures that are most likely to occur in nature. In this paper, we propose a novel procedure to improve the predictive performances of computational scoring protocols, using a maximum likelihood estimate based on topological and electrical properties of interacting biomolecules. The reliability of the new computational approach, enabling the ranking of aptamer−protein configurations produced by an open source docking program, has been assessed by its successful application to a set of antiangiopoietin aptamers, for which experimental data highlighting the sequence-dependent affinity toward the target protein are available. The procedure led to the identification of two main types of aptamer conformers involved in angiopoietin binding. Interestingly, one of these reproduces the arrangement of angiopoietin with its natural target, tyrosine kinase, while the other one is completely unexpected. The possible scenarios related to these results have been discussed. The methodology here described can be used to refine the outcomes of different computational procedures and can be applied to a wide range of biological molecules, thus representing a new tool for guiding the design of bioinspired sensors with enhanced selectivity.

Biosensing Cytokine IL-6: A Comparative Analysis of Natural and Synthetic Receptors

“…The topology of the biomolecule (receptor, ligand, or their complex) is investigated through its equivalent network [ 38 ]. A pair of ideal contacts is used to connect the network to an external battery, working in D.C., and in the linear regime [ 37 , 38 , 53 ]. In this way, an electron current flows inside the biomolecule equivalent network, thus detecting its internal structure [ 41 , 42 ].…”

“…We used an investigation technique named Proteotronics [ 32 , 36 , 37 , 38 , 53 ] which explores the electronic responses of biomolecules by using a complex network approach. The technique is intuitive and simple to use.…”

“…Besides, they have outstanding performances in terms of affinity and stability, both in vitro and in vivo [ 30 , 31 ]. Furthermore, the interest in pharmaceutics [ 32 ] has pushed forward the investigation of their 3D structure with crystallographic analysis [ 28 , 33 , 34 ] and computational analysis [ 35 , 36 , 37 ].…”

“…To this aim, each link is associated with specific impedance elements [ 38 ] and an electrical current is allowed to flow through the network. This kind of theoretical probing is able to detect the internal structure of the network and, in particular, to reveal the presence of short-paths or bottlenecks [ 37 , 38 ]. In the present case, the spreading of the current flow aims to detect the quality of the binding.…”

Focus on In Silico Aptamer Synthesis New Food for Thought

“…The procedure proposes hundreds of configurations for each sequence, whose mean properties were analyzed by using a complex network approach called Proteotronics [11,12]. In a nutshell, each complex was mapped into an impedance network whose topological and electrical features were used to produce an alternate ranking based on a novel indicator, Möbius (M) [13]. The mean features of each aptamer were in reasonable agreement with experimental data.9 However, after a deeper investigation, it clearly appeared that the samples given by the numerical procedure were not homogeneous.…”