Electrostatics in Computational Biophysics and Its Implications for Disease Effects

Abstract

This review outlines the role of electrostatics in computational molecular biophysics and its implication in altering wild-type characteristics of biological macromolecules, and thus the contribution of electrostatics to disease mechanisms. The work is not intended to review existing computational approaches or to propose further developments. Instead, it summarizes the outcomes of relevant studies and provides a generalized classification of major mechanisms that involve electrostatic effects in both wild-type and mutant biological macromolecules. It emphasizes the complex role of electrostatics in molecular biophysics, such that the long range of electrostatic interactions causes them to dominate all other forces at distances larger than several Angstroms, while at the same time, the alteration of short-range wild-type electrostatic pairwise interactions can have pronounced effects as well. Because of this dual nature of electrostatic interactions, being dominant at long-range and being very specific at short-range, their implications for wild-type structure and function are quite pronounced. Therefore, any disruption of the complex electrostatic network of interactions may abolish wild-type functionality and could be the dominant factor contributing to pathogenicity. However, we also outline that due to the plasticity of biological macromolecules, the effect of amino acid mutation may be reduced, and thus a charge deletion or insertion may not necessarily be deleterious.

How does the ion concentration affect the functions of kinesin BimC

“…It indicates that the electrostatic interactions is a key factor of the BimC-microtubule interactions. Deep understanding of the functions of such hot spot residues may help guide kinesin-targeted anticancer drug design [41][42][43][44][45][46]. Combining computational and experimental results to comprehensively understand the BimC-microtubule interaction is a promising approach to investigating the fundamental mechanisms underlying was not certified by peer review) is the author/funder.…”

A role for pH dynamics regulating transcription factor DNA binding selectivity

“…The copyright holder for this preprint (which this version posted May 21, 2024. ; https://doi.org/10.1101/2024.05. 21.595212 doi: bioRxiv preprint gene expression. Additionally, we used unbiased approaches of SELEX-seq and RNA-seq to identify different DNA motif binding profiles at lower pH (7.0-7.4) compared with higher pH (7.7-7.8).…”

“…Although changes in pHi were previously viewed as a mechanism to maintain homeostasis, it is now known that changes in pHi occur and are necessary for normal cell processes such as cell cycle progression for proliferation [1][2][3] , actin filament and cell-substrate adhesion remodeling for directed cell migration [4][5][6][7][8][9] , and stem cell differentiation and lineage specification [10][11][12] . Moreover, it is now established that pHi dynamics is dysregulated in human diseases, including cancer 13-dynamics regulates normal and pathological cell behaviours is often mediated by protein electrostatics and the protonation state of key residues in endogenous pH sensitive proteins termed "pH sensors" 20,21 .…”

“…Our findings identify pH-regulated transcription factor-DNA binding selectivity with relevance to how pHi dynamics can regulate gene expression for myriad cell behaviours.15 , diabetes 16,17 , and neurodegeneration 18,19 . The molecular mechanisms by which pHi dynamics regulates normal and pathological cell behaviours is often mediated by protein electrostatics and the protonation state of key residues in endogenous pH sensitive proteins termed "pH sensors" 20,21 .Of all amino acids that undergo protonation state changes in solution, histidine side chains exhibit the closest pKa (6.5) to physiological pH. However, the pKa of histidine, aspartic acid, glutamic acid, and buried lysine can be upshifted or downshifted depending on the protein electrostatics environment to enable titration within the cellular pH range of 7.0-7.8 6,22,23 .Changes in the protonation state of key amino acids in response to small changes in pH (0.2-0.3) can significantly alter protein structure and function, including activity 7,24-26 and ligand binding 5,6,[27][28][29] as well as stability 30-32 and aggregation 33,34 .…”

A Comprehensive Study on the Electrostatic Properties of Tubulin-Tubulin Complexes in Microtubules

“…Computational methods have been widely used to study the functions of biomolecules [25][26][27][28][29] including tubulins. Dr. Alberto Redaelli's group evaluated the elastic constants of an α-/β-tubulin monomer and the interaction force between the components by means of molecular dynamics simulations, and constructed a mechanical model of the tubulin dimer [30]; Joshi and Dima studied the microscopic origins of the mechanical response in microtubules by probing features of the energy landscape of the tubulin monomers and tubulin heterodimer with molecular simulations [31]; Marracino's group explored the response of tubulin to strong electric fields at the nanosecond level in molecular dynamics simulations [32]; Dr. Aristide Dogariu' lab reported accurate optical measurements of tubulin polarizability in aqueous suspensions [33]; Andriy Kovalenko et al studied the microtubule stability by using the three-dimensional molecular theory of solvation [34].…”