Classical Electrostatics in Biology and Chemistry

Honig, Barry; Nicholls, Anthony

doi:10.1126/science.7761829

Cited by 2,754 publications

(2,539 citation statements)

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“…Anoxia and acidosis are cardinal features of hepatic ischemia. Alterations in pH can perturb activity, structure, and conformation of proteins (Honig & Nicholls, 1995). As mitochondria have an alkaline environment, one possibility is that acidic pH could destabilize mitochondrial proteins.…”

Section: Discussionmentioning

confidence: 99%

Loss of sirtuin 1 and mitofusin 2 contributes to enhanced ischemia/reperfusion injury in aged livers

et al. 2018

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SummaryIschemia/reperfusion (I/R) injury is a causative factor contributing to morbidity and mortality during liver resection and transplantation. Livers from elderly patients have a poorer recovery from these surgeries, indicating reduced reparative capacity with aging. Mechanisms underlying this age‐mediated hypersensitivity to I/R injury remain poorly understood. Here, we investigated how sirtuin 1 (SIRT1) and mitofusin 2 (MFN2) are affected by I/R in aged livers. Young (3 months) and old (23–26 months) male C57/BL6 mice were subjected to hepatic I/R in vivo. Primary hepatocytes isolated from each age group were also exposed to simulated in vitro I/R. Biochemical, genetic, and imaging analyses were performed to assess cell death, autophagy flux, mitophagy, and mitochondrial function. Compared to young mice, old livers showed accelerated liver injury following mild I/R. Reperfusion of old hepatocytes also showed necrosis, accompanied with defective autophagy, onset of the mitochondrial permeability transition, and mitochondrial dysfunction. Biochemical analysis indicated a near‐complete loss of both SIRT1 and MFN2 after I/R in old hepatocytes, which did not occur in young cells. Overexpression of either SIRT1 or MFN2 alone in old hepatocytes failed to mitigate I/R injury, while co‐overexpression of both proteins promoted autophagy and prevented mitochondrial dysfunction and cell death after reperfusion. Genetic approaches with deletion and point mutants revealed that SIRT1 deacetylated K655 and K662 residues in the C‐terminus of MFN2, leading to autophagy activation. The SIRT1‐MFN2 axis is pivotal during I/R recovery and may be a novel therapeutic target to reduce I/R injury in aged livers.

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Section: Discussionmentioning

confidence: 99%

Loss of sirtuin 1 and mitofusin 2 contributes to enhanced ischemia/reperfusion injury in aged livers

et al. 2018

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“…The remaining effects are small beyond e = 6, which is in the lower end of the shielding anticipated for a protein environment, 4-16. 48 Thus, we consider 2.60Å the equilibrium non-strained Cd-S bond length and 2.39Å the non-strained Zn-S bond length for these tetrahedral sites and use e = 10 in our calculations.…”

Section: Non-strained Structures and Effect Of Screeningmentioning

confidence: 99%

The building blocks of metallothioneins: heterometallic Zn2+ and Cd2+ clusters from first-principles calculations

Jensen

Rykær

2010

Dalton Trans.

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Electronic structures of Zn 2+ and Cd 2+ thiolate clusters found in metallothioneins (MT) have been obtained using density functional theory. We have found that the inherent asymmetry of cluster architectures gives rise to seven distinct metal sites. Whereas the non-strained bond lengths of such tetrathiolate complexes are found to be 2.60Å and 2.39Å for Cd-S and Zn-S, in the MT clusters four characteristic terminal and bridging bonds are observed with average lengths 2.55Å (Cd-S t ); 2.35Å (Zn-S t ); 2.62Å (Cd-S b ); and 2.42Å (Zn-S b ). For each stoichiometry of Zn 2+ and Cd 2+ , all possible isomers have been characterized and ranked according to relative free energy and metal ion selectivity. The most stable distribution at low Cd 2+ concentration is computed to be Zn 4 + CdZn 2 , whereas at 2 : 1 Cd 2+ : Zn 2+ concentration, only heteroclusters are thermodynamically stable, explaining experimental data. The presence of two different clusters in MTs must and can be rationalized already in their intrinsic differences. The results indicate that the asymmetry allows for Zn 2+ transfer to various molecular targets having different thresholds for Zn 2+ binding, while maintaining detoxification sites.

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“…Electrostatic interactions in water often defy simple intuition: like charges can attract, and unlike charges repel (Honig & Nicholls, 1995;Gitlin et al 2006). Underlying electrostatic interactions in water is Coulomb's law, but this most familiar of expressions must be modified by solvation.…”

Section: Interactions: Coulomb's Law In Watermentioning

confidence: 99%

Designing ligands to bind proteins

Whitesides

Krishnamurthy

2005

Quart. Rev. Biophys.

123

108

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The ability to design drugs (so-called 'rational drug design') has been one of the long-term objectives of chemistry for 50 years. It is an exceptionally difficult problem, and many of its parts lie outside the expertise of chemistry. The much more limited problem -how to design tight-binding ligands (rational ligand design) -would seem to be one that chemistry could solve, but has also proved remarkably recalcitrant. The question is 'Why is it so difficult?' and the answer is 'We still don't entirely know'. This perspective discusses some of the technical issues -potential functions, protein plasticity, enthalpy/entropy compensation, and others -that contribute, and suggests areas where fundamental understanding of protein-ligand interactions falls short of what is needed. It surveys recent technological developments (in particular, isothermal titration calorimetry) that will, hopefully, make now the time for serious progress in this area. It concludes with the calorimetric examination of the association of a series of systematically varied ligands with a model protein. The counterintuitive thermodynamic results observed serve to illustrate that, even in relatively simple systems, understanding protein-ligand association is challenging. Rational ligand designMolecular recognition is, in a sense, the most important process in molecular biology. Most of the reactions and interactions that dominate the operation of living systems -recognition of sequences in nucleic acids by complementary nucleic acids and by proteins; folding of proteins; recognition of ligands by proteins; interaction of drugs and target proteins; differential stabilization of the transition state and ground state of biochemical reactions by enzymes; many others -involve molecular recognition. Understanding molecular recognition is centrally important to understanding -and controlling -the set of molecular processes that make up the cell, and life.The problem of understanding molecular recognition translates, in utilitarian terms, into being able to design ligands that bind to specific sites on biomacromolecules (most often, proteins). This problem is intellectually enormously interesting, since solving it would provide ways of modulating the activities of proteins in vivo. More practically, it is central to the idea of socalled 'rational drug design'. Generating drugs has been, and remains, a difficult, expensive, failure-prone, and highly empirical activity. The difficulty and cost of developing new drugs has become prohibitive for the pharmaceutical industry, and without improved efficiency and productivity from the R&D groups of this industry, there is a widespread concern that the rate at which new drugs will be developed in the future will be substantially less than it has been in the past. The process of generating a drug is, of course, much more complicated than simply designing a ligand that targets a protein: 'hits' and 'leads' are an important part of the process, but ADME/Tox/PK/PD (adsorption, distribution, metabolism, excre...

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Classical Electrostatics in Biology and Chemistry

Cited by 2,754 publications

References 104 publications

Loss of sirtuin 1 and mitofusin 2 contributes to enhanced ischemia/reperfusion injury in aged livers

Loss of sirtuin 1 and mitofusin 2 contributes to enhanced ischemia/reperfusion injury in aged livers

The building blocks of metallothioneins: heterometallic Zn2+ and Cd2+ clusters from first-principles calculations

Designing ligands to bind proteins

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