Role of the C-terminal chain in human interferonγ stability: An electrostatic study
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Electrostatic interactions in two structures of human interferon gamma (hIFNγ), corresponding to interferon molecule alone and bound to its receptor, were analyzed on the basis of a continuum dielectric model. It was found that a number of titratable groups, mainly basic, show large pK shifts and remain in their neutral forms at physiologically relevant pH. The fact that these groups are largely common to both structures and that most of them belong to the set of most conserved sites suggests that this is a property inherent to the hIFNγ molecule rather than an artifact of the crystal packing. His111 was also found deprotonated at neutral pH. It was concluded that receptor recognition involving His111 is driven by aromatic coupling of His111 and Tyr52 from the receptor rather than by electrostatic interactions. The structure corresponding to hIFNγ in complex with its receptor shows a reduction in number and in degree of desolvation of the buried titratable sites. This finding suggested that on receptor binding, hIFNγ adopts energetically more favorable, relaxed, conformation. It was experimentally shown that in contrast to the full-size hIFNγ, the construct having 21 amino acid residues deleted from the C-terminus is soluble. The hydrophobicity profile analysis suggested that factors other than the exposure of hydrophobic parts of the molecule are responsible for the low stability and propensity for aggregation. On the basis of these results, it was assumed that the electrostatic influence of the C-terminal part contributes particularly to the low solvent exposure of the titratable groups, and hence to the low structural stability and propensity for aggregation of the recombinant hIFNγ. Proteins 2001;43:125–133. © 2001 Wiley-Liss, Inc.Keywords:
Titratable acid
Static electricity
Electrostatics
While being long in range and therefore weakly specific, electrostatic interactions are able to modulate the stability and folding landscapes of some proteins. The relevance of electrostatic forces for steering the docking of proteins to each other is widely acknowledged, however, the role of electrostatics in establishing specifically funneled landscapes and their relevance for protein structure prediction are still not clear. By introducing Debye-Hückel potentials that mimic long-range electrostatic forces into the Associative memory, Water mediated, Structure, and Energy Model (AWSEM), a transferable protein model capable of predicting tertiary structures, we assess the effects of electrostatics on the landscapes of thirteen monomeric proteins and four dimers. For the monomers, we find that adding electrostatic interactions does not improve structure prediction. Simulations of ribosomal protein S6 show, however, that folding stability depends monotonically on electrostatic strength. The trend in predicted melting temperatures of the S6 variants agrees with experimental observations. Electrostatic effects can play a range of roles in binding. The binding of the protein complex KIX-pKID is largely assisted by electrostatic interactions, which provide direct charge-charge stabilization of the native state and contribute to the funneling of the binding landscape. In contrast, for several other proteins, including the DNA-binding protein FIS, electrostatics causes frustration in the DNA-binding region, which favors its binding with DNA but not with its protein partner. This study highlights the importance of long-range electrostatics in functional responses to problems where proteins interact with their charged partners, such as DNA, RNA, as well as membranes.
Electrostatics
Static electricity
Energy landscape
Folding (DSP implementation)
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The observation and research on electrostatic phenomena by the ancients, and the formation of electrostatics theory are summarized. The development trends from traditional static electricity to current electrostatic problems are explained. Electrostatic protection engineering related to static electricity on human body, electrostatic discharge and electromagnetic radiation is discussed. Researches on the mechanism of electrostatic electrification, electrostatic discharge models, electrostatic hazards and protection, electrostatic measurement techniques are presented.
Electrostatics
Static electricity
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The role of electrostatics in protein–protein interactions and binding is reviewed in this paper. A brief outline of the computational modeling, in the framework of continuum electrostatics, is presented and the basic electrostatic effects occurring upon the formation of the complex are discussed. The effect of the salt concentration and pH of the water phase on protein–protein binding free energy is demonstrated which indicates that the increase of the salt concentration tends to weaken the binding, an observation that is attributed to the optimization of the charge–charge interactions across the interface. It is pointed out that the pH-optimum (pH of optimal binding affinity) varies among the protein–protein complexes, and perhaps is a result of their adaptation to particular subcellular compartments. The similarities and differences between hetero- and homo-complexes are outlined and discussed with respect to the binding mode and charge complementarity.
Electrostatics
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Complementarity (molecular biology)
Electrostatic interaction
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Protein electrostatic properties stem from the proportion and distribution of polar and charged residues. Polar and charged residues regulate the electrostatic properties by forming shortrange interactions, like salt-bridges and hydrogen-bonds, and by defining the over-all electrostatic environment in the protein. Electrostatics play a major role in defining the mechanisms of proteinprotein complex formation, molecular recognitions, thermal stabilities, conformational adaptabilities and protein movements. For example:- Functional hinges, or flexible regions of the protein, lack short-range electrostatic interactions, Thermophilic proteins have higher electrostatic interactions than their mesophilic counter parts, Increase in binding specificity and affinity involve optimization of electrostatics, High affinity antibodies have higher, and stronger, electrostatic interactions with their antigens, Rigid parts of proteins have higher and stronger electrostatic interactions. In this review we address the significance of electrostatics in protein folding, binding and function. We discuss that the electrostatic properties are evolutionally selected by a protein to perform an specific function. We also provide bona fide examples to illustrate this. Additionally, using continuum electrostatic and molecular dynamics approaches we show that the “hot-spot” inter-molecular interactions in a very specific antibody-antigen binding are mainly established through charged residues. These “hot-spot” molecular interactions stay intact even during high temperature molecular dynamics simulations, while the other inter-molecular interactions, of lesser functional significance, disappear. This further corroborates the significance of charge-charge interactions in defining binding mechanisms. High affinity binding frequently involves “electrostatic steering”. The forces emerge from over-all electrostatic complementarities and by the formation of charged a nd polar interactions. We demonstrate that although the high affinity binding of barnase-barstar and anti-hen egg white lysozyme (HEL) antibody-HEL complexes involve different molecular mechanisms, it is electrostatically regulated in both the cases. These observations, and several other studies, suggest that a fine tuning of local and global electrostatic properties are essential for protein binding and function. Keywords: Electrostatics, Protein, lysozyme, Molecular dynamics, Lumazine synthase, Glutamate dehydrogenase, HyHEL antibody
Electrostatics
Static electricity
Hydrophobic effect
Electrostatic interaction
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Electrostatics
Static electricity
Salt bridge
Barnase
Hydrophobic effect
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Electrostatics
Static electricity
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Electrostatics
Static electricity
Electrostatic interaction
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Electrostatics plays a key role in biomolecular assembly. Oppositely charged biomolecules, for instance, can co-assembled into functional units, such as DNA and histone proteins into nucleosomes and actin-binding protein complexes into cytoskeleton components, at appropriate ionic conditions. These cationic-anionic co-assemblies often have surface charge heterogeneities that result from the delicate balance between electrostatics and packing constraints. Despite their importance, the precise role of surface charge heterogeneities in the organization of cationic-anionic co-assemblies is not well understood. We show here that co-assemblies with charge heterogeneities strongly interact through polarization of the domains. We find that this leads to symmetry breaking, which is important for functional capabilities, and structural changes, which is crucial in the organization of co-assemblies. We determine the range and strength of the attraction as a function of the competition between the steric and hydrophobic constraints and electrostatic interactions.
Electrostatics
Cationic polymerization
Static electricity
Biomolecule
Surface charge
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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.
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A continuum electrostatics model is used to calculate the relative stabilities of 117 mutants of staphylococcal nuclease (SNase) involving the mutation of a charged residue to an uncharged residue.The calculations are based on the crystallographic structure of the wild-type protein and attempt to take implicitly into account the effect of the mutations in the denatured state by assuming a linear relationship between the free energy changes caused by the mutation in the native and denatured states.A good correlation (linear correlation coef®cient of ~0.8) is found with published experimental relative stabilities of these mutants.The results suggest that in the case of SNase (i) charged residues contribute to the stability of the native state mainly through electrostatic interactions, and (ii) native-like electrostatic interactions may persist in the denatured state.The continuum electrostatics method is only moderately sensitive to model parameters and leads to quasi-predictive results for the relative mutant stabilities (error of 2±3 kJ mol ±1 or of the order of k B T), except for mutants in which a charged residue is mutated to glycine.
Electrostatics
Static electricity
Nuclease
Residue (chemistry)
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