Sebastián R. Accordino

Quantitative investigation of the two-state picture for water in the normal liquid and the supercooled regime

Several evidences have helped to establish the two-state nature of liquid water. Thus, within the normal liquid and supercooled regimes water has been shown to consist of a mixture of well-structured, low-density molecules and unstructured, high-density ones. However, quantitative analyses have faced the burden of unambiguously determining both the presence and the fraction of each kind of water “species”. A recent approach by combining a local structure index with potential-energy minimisations allows us to overcome this difficulty. Thus, in this work we extend such study and employ it to quantitatively determine the fraction of structured molecules as a function of temperature for different densities. This enables us to validate predictions of two-state models.

Hydrophilic behavior of graphene and graphene-based materials

Graphene and the graphene-based materials like graphite, carbon nanotubes, and fullerenes are not only usually regarded as hydrophobic but also have been widely employed as paradigms for the investigation of the behavior of water under nonpolar confinement, a question of major concern for fields ranging from biology to materials design. However, some experimental and theoretical insights seem to contradict, at least partially, such a picture. In this work, we will provide firm evidence for a neat hydrophilic nature of graphene surfaces. Our molecular dynamics studies will demonstrate that parallel graphene sheets present a strong tendency to remain fully hydrated for moderately long times (even when the equilibrium state is indeed the collapse of the plates), and thus, they are less prone to self-assembly than model hydrophobic surfaces we shall employ as control which readily undergo a hydrophobic collapse. Potential of mean force calculations will indeed make evident that the solvent exerts a repulsive contribution on the self-assembly of graphene surfaces. Moreover, we shall also quantify graphene hydrophilicity by means of the calculation of water density at two pressures and water density fluctuations. This latter study has never been performed on graphene and represents a means both to confirm and to quantify its neat hydrophilic behavior. We shall also make evident the relevance of the mildly attractive water-carbon interactions, since their artificial weakening will be shown to revert from typically hydrophilic to typically hydrophobic behavior.

Wrapping mimicking in drug-like small molecules disruptive of protein–protein interfaces

The discovery of small‐molecule drugs aimed at disrupting protein–protein associations is expected to lead to promising therapeutic strategies. The small molecule binds to the target protein thus replacing its natural protein partner. Noteworthy, structural analysis of complexes between successful disruptive small molecules and their target proteins has suggested the possibility that such ligands might somehow mimic the binding behavior of the protein they replace. In these cases, the molecules show a spatial and “chemical” (i.e., hydrophobicity) similarity with the residues of the partner protein involved in the protein–protein complex interface. However, other disruptive small molecules do not seem to show such spatial and chemical correspondence with the replaced protein. In turn, recent progress in the understanding of protein–protein interactions and binding hot spots has revealed the main role of intermolecular wrapping interactions: three‐body cooperative correlations in which nonpolar groups in the partner protein promote dehydration of a two‐body electrostatic interaction of the other protein. Hence, in the present work, we study some successful complexes between already discovered small disruptive drug‐like molecules and their target proteins already reported in the literature and we compare them with the complexes between such proteins and their natural protein partners. Our results show that the small molecules do in fact mimic to a great extent the wrapping behavior of the protein they replace. Thus, by revealing the replacement the small molecule performs of relevant wrapping interactions, we convey precise physical meaning to the mimicking concept, a knowledge that might be exploited in future drug‐design endeavors. Proteins 2012.

Protein packing defects “heat up” interfacial water

Ligands must displace water molecules from their corresponding protein surface binding site during association. Thus, protein binding sites are expected to be surrounded by non-tightly-bound, easily removable water molecules. In turn, the existence of packing defects at protein binding sites has been also established. At such structural motifs, named dehydrons, the protein backbone is exposed to the solvent since the intramolecular interactions are incompletely wrapped by non-polar groups. Hence, dehydrons are sticky since they depend on additional intermolecular wrapping in order to properly protect the structure from water attack. Thus, a picture of protein binding is emerging wherein binding sites should be both dehydrons rich and surrounded by easily removable water. In this work we shall indeed confirm such a link between structure and dynamics by showing the existence of a firm correlation between the degree of underwrapping of the protein chain and the mobility of the corresponding hydration water molecules. In other words, we shall show that protein packing defects promote their local dehydration, thus producing a region of “hot” interfacial water which might be easily removed by a ligand upon association.Graphical abstract

A unifying motif of intermolecular cooperativity in protein associations

At the molecular level, most biological processes entail protein associations which in turn rely on a small fraction of interfacial residues called hot spots. Our theoretical analysis shows that hot spots share a unifying molecular attribute: they provide a third-body contribution to intermolecular cooperativity. Such motif, based on the wrapping of interfacial electrostatic interactions, is essential to maintain the integrity of the interface. Thus, our main result is to unravel the molecular nature of the protein association problem by revealing its underlying physics and thus by casting it in simple physical grounds. Such knowledge could then be exploited in rational drug design since the regions here indicated may serve as blueprints to engineer small molecules disruptive of protein-protein interfaces.

Wrapping Effects within a Proposed Function-Rescue Strategy for the Y220C Oncogenic Mutation of Protein p53

Soluble proteins must protect their structural integrity from water attack by wrapping interactions which imply the clustering of nonpolar residues around the backbone hydrogen bonds. Thus, poorly wrapped hydrogen bonds constitute defects which have been identified as promoters of protein associations since they favor the removal of hydrating molecules. More specifically, a recent study of our group has shown that wrapping interactions allow the successful identification of protein binding hot spots. Additionally, we have also shown that drugs disruptive of protein-protein interfaces tend to mimic the wrapping behavior of the protein they replace. Within this context, in this work we study wrapping three body interactions related to the oncogenic Y220C mutation of the tumor suppressor protein p53. Our computational results rationalize the oncogenic nature of the Y220C mutation, explain the binding of a drug-like molecule already designed to restore the function of p53 and provide clues to help improve this function-rescue strategy and to apply in other drug design or re-engineering techniques.

“Chameleonic” backbone hydrogen bonds in protein binding and as drug targets

We carry out a time-averaged contact matrix study to reveal the existence of protein backbone hydrogen bonds (BHBs) whose net persistence in time differs markedly form their corresponding PDB-reported state. We term such interactions as “chameleonic” BHBs, CBHBs, precisely to account for their tendency to change the structural prescription of the PDB for the opposite bonding propensity in solution. We also find a significant enrichment of protein binding sites in CBHBs, relate them to local water exposure and analyze their behavior as ligand/drug targets. Thus, the dynamic analysis of hydrogen bond propensity might lay the foundations for new tools of interest in protein binding-site prediction and in lead optimization for drug design.Graphical abstract

Hydrogen Bond Dynamic Propensity Studies for Protein Binding and Drug Design

We study the dynamic propensity of the backbone hydrogen bonds of the protein MDM2 (the natural regulator of the tumor suppressor p53) in order to determine its binding properties. This approach is fostered by the observation that certain backbone hydrogen bonds at the p53-binding site exhibit a dynamical propensity in simulations that differs markedly form their state-value (that is, formed/not formed) in the PDB structure of the apo protein. To this end, we conduct a series of hydrogen bond propensity calculations in different contexts: 1) computational alanine-scanning studies of the MDM2-p53 interface; 2) the formation of the complex of MDM2 with the disruptive small molecule Nutlin-3a (dissecting the contribution of the different molecular fragments) and 3) the binding of a series of small molecules (drugs) with different affinities for MDM2. Thus, the relevance of the hydrogen bond propensity analysis for protein binding studies and as a useful tool to complement existing methods for drug design and optimization will be made evident.

Studies on electrostatic interactions within model nano-confined aqueous environments of different chemical nature

Abstract.We study the potential of mean force for pairs of parallel flat surfaces with attractive electrostatic interactions by employing model systems functionalized with different charged, hydrophobic and hydrophilic groups. We study the way in which the local environment (hydrophobic or hydrophilic moieties) modulates the interaction between the attractive charged groups on the plates by removing or attracting nearby water and thus screening or not the electrostatic interaction. To explicitly account for the role of the solvent and the local hydrophobicity, we also perform studies in vacuo. Additionally, the results are compared to that for non-charged plates in order to single out and rationalize the non-additivity of the different non-covalent interactions. Our simulations demonstrate that the presence of neighboring hydrophobic groups promote water removal in the vicinity of the charged groups, thus enhancing charge attraction upon self-assembly. This role of the local hydrophobicity modulating electrostatic interactions is consistent with recent qualitative descriptions in the protein binding context.Graphical abstract

Design, synthesis and biological evaluation of 1,3-dihydroxyxanthone derivatives: Effective agents against acetylcholinesterase

The present work concerns the rational design and development of new inhibitors of acetylcholinesterase (AChE) based on the privileged xanthone scaffold. In order to understand and rationalize the mode of action of these target structures a theoretical study was initially conducted. From the results of rational design, a new variety of amphiphilic xanthone derivatives were synthesized, structurally characterized and evaluated as potential anti-Alzheimer agents. The results showed that most of the synthesized compounds exhibited high AChE inhibitory activity at the micromolar range (IC50, 0.46-12.09μM). The synthetic xanthone 11 showed the best inhibitory effect on AChE and a molecular modeling study revealed that 11 targeted both the catalytic active site (CAS) and the peripheral anionic site (PAS) of AChE. Therefore, this compound could be considered asa potential lead compound towards new drugs for the treatment of Alzheimers disease.