Protein electrostatics: From computational and structural analysis to discovery of functional fingerprints and biotechnological design

Abstract

Computationally driven engineering of proteins aims to allow them to withstand an extended range of conditions and to mediate modified or novel functions. Therefore, it is crucial to the biotechnological industry, to biomedicine and to afford new challenges in environmental sciences, such as biocatalysis for green chemistry and bioremediation. In order to achieve these goals, it is important to clarify molecular mechanisms underlying proteins stability and modulating their interactions. So far, much attention has been given to hydrophobic and polar packing interactions and stability of the protein core. In contrast, the role of electrostatics and, in particular, of surface interactions has received less attention. However, electrostatics plays a pivotal role along the whole life cycle of a protein, since early folding steps to maturation, and it is involved in the regulation of protein localization and interactions with other cellular or artificial molecules. Short- and long-range electrostatic interactions, together with other forces, provide essential guidance cues in molecular and macromolecular assembly. We report here on methods for computing protein electrostatics and for individual or comparative analysis able to sort proteins by electrostatic similarity. Then, we provide examples of electrostatic analysis and fingerprints in natural protein evolution and in biotechnological design, in fields as diverse as biocatalysis, antibody and nanobody engineering, drug design and delivery, molecular virology, nanotechnology and regenerative medicine.

Comparative molecular dynamics study of the receptor-binding domains in SARS-CoV-2 and SARS-CoV and the effects of mutations on the binding affinity

“…The electrostatics also regulates protein interactions with other proteins as well as with molecules other than proteins, such as small-molecule drugs (Voet et al., 2013 ). The electrostatic features of the protein are determined by the distribution of whole and partial charges across the 3D protein structure (Vascon et al., 2020 ). Here, Coulomb’s law is not appropriate for describing electrostatic effects in proteins because it applies to a system with uniform dielectric properties, whilst proteins dispersed in a medium display a gradient dielectric constant, with a hydrophobic core surrounded by the hydrophilic surface and covered by the solvent.…”

“…Here, Coulomb’s law is not appropriate for describing electrostatic effects in proteins because it applies to a system with uniform dielectric properties, whilst proteins dispersed in a medium display a gradient dielectric constant, with a hydrophobic core surrounded by the hydrophilic surface and covered by the solvent. Hence, electrostatic calculations for proteins were carried out using the Poisson-Boltzmann equation (Vascon et al., 2020 ).…”

Molecular Dynamics Simulations in Designing DARPins as Phosphorylation-Specific Protein Binders of ERK2

“…Knowledge about the charge distributions can be useful in determining how molecules interact with one another. Moreover, electrostatic forces help in fast recognizing the right partner among hundreds of thousands of candidates present in the intracellular environment of protein-protein complexes [ 62 ].…”

Decoding nonspecific interactions between human nuclear transport proteins: A computational study

“…Additionally, they also play crucial role in molecular recognition events ( Hildebrandt et al, 2007 ). Furthermore, for proper folding of nascent proteins and their stability, as well as in enzyme catalytic reactions, electrostatic forces play pivotal role ( Vascon et al, 2020) . Figure 2 represents the electrostatic potential surface of each transport protein.…”