Showing papers on "Salt bridge (protein and supramolecular) published in 2012"

Specific noncovalent interactions at protein-ligand interface: implications for rational drug design

Abstract: Specific noncovalent interactions that are indicative of attractive, directional intermolecular forces have always been of key interest to medicinal chemists in their search for the "glue" that holds drugs and their targets together. With the rapid increase in the number of solved biomolecular structures as well as the performance enhancement of computer hardware and software in recent years, it is now possible to give more comprehensive insight into the geometrical characteristics and energetic landscape of certain sophisticated noncovalent interactions present at the binding interface of protein receptors and small ligands based on accumulated knowledge gaining from the combination of two quite disparate but complementary approaches: crystallographic data analysis and quantum-mechanical ab initio calculation. In this perspective, we survey massive body of published works relating to structural characterization and theoretical investigation of three kinds of strong, specific, direct, enthalpy-driven intermolecular forces, including hydrogen bond, halogen bond and salt bridge, involved in the formation of protein-ligand complex architecture in order to characterize their biological functions in conferring affinity and specificity for ligand recognition by host protein. In particular, the biomedical implications of raised knowledge are discussed with respect to potential applications in rational drug design.

Ionic Liquid Salt Bridge with Low Solubility of Water and Stable Liquid Junction Potential Based on a Mixture of a Potential-Determining Salt and a Highly Hydrophobic Ionic Liquid

Abstract: A new type of ionic liquid salt bridge(ILSB) based on a mixture of pentyltripropylammonium bis(pentafluoroethanesulfonyl)amide, [N3335+][C2C2N–], and heptadecafluorodecyltrioctylphosphonium tetraki...

Role of arginine 29 and glutamic acid 81 interactions in the conformational stability of human chloride intracellular channel 1

Abstract: The ion channel protein CLIC1 exists in both a soluble conformation in the cytoplasm and a membrane-bound conformation. The conformational stability of soluble CLIC1 demonstrates pH sensitivity which may be attributable to very specific residues that function as pH sensors. These sensors could be histidine or glutamate residues with pK(a) values that fall within the physiological pH range. The role of Glu81, a member of a topologically conserved buried salt bridge in CLIC1, as a pH sensor was investigated here. The mutants E81M, R29M, and E81M/R29M were designed to break the salt bridge between Glu81 and Arg29 and examine the effect of each member on the stability of the protein. Spectroscopic studies and the solved crystal structures indicated that the global structure of CLIC1 was not affected by the mutations. Urea-induced equilibrium unfolding unexpectedly showed E81M to stabilize CLIC1 at pH 7. This was due to stabilizing hydrophobic interactions with Met81 and a water-mediated compensatory H-bond between Met81 and Arg29. R29M and E81M/R29M destabilized CLIC1 at pH 7, and the unfolding transition changed from two-state to three-state, mimicking the wild type at pH 5.5. This observation points out the significance of the salt bridge in stabilizing the native state. The total unfolding free energy change of E81M CLIC1 does not change with pH, implying that Glu81 forms one of a network of pH-sensor residues in CLIC1 responsible for destabilization of the native state. This allows detachment of the N-domain from the C-domain at low pH.

The role of Lys147 in the interaction between MPSA-gold nanoparticles and the α-hemolysin nanopore.

Abstract: Single channel recordings were used to determine the effect of direct electrostatic interactions between sulfonate-coated gold nanoparticles and the constriction of the Staphylococcus aureus α-hemolysin protein channel on the ionic current amplitude. We provide evidence that Lys147 of α- hemolysin can interact with the sulfonate groups at the nanoparticle surface, and these interactions can reversibly block 100% of the residual ionic current. Lys147 is normally involved in a salt bridge with Glu111. The capture of a nanoparticle leads to a partial current block at neutral pH values, but protonation of Glu111 at pH 2.8 results in a full current block when the nanoparticle is captured. At pH 2.8, we suggest that Lys147 is free to engage in electrostatic interactions with sulfonates at the nanoparticle surface. To verify our results, we engineered a mutation in the α-hemolysin protein, where Glu111 is substituted by Ala (E111A), thus removing Glu111−Lys147 interactions and facilitating Lys147− sulfonate electrostatic interactions. This mutation leads to a 100% current block at pH 2.8 and a 92% block at pH 8.0, showing that electrostatic interactions are formed between the nanopore and the nanoparticle surface. Besides demonstrating the effect of electrostatic interactions on cross channel ionic current, this work offers a novel approach to controlling open and closed states of the α-hemolysin nanopore as a function of external gears.

Infrared spectra of charge‐solvated versus salt‐bridge conformations of glycine‐, serine‐, and cysteine‐Ca2+ complexes

Abstract: The structure, relative stability, and anharmonic vibrational frequencies of the most stable complexes between glycine, serine, and cysteine with Ca2+ have been calculated by means of DFT approaches. The global minimum of the potential energy surface for glycine-Ca2+ complex corresponds to the salt-bridge (SB) form, whereas for serine- and cysteine-Ca2+ complexes is a charge-solvated (CS) structure in which the metal dication is bound to the carbonyl group of the acidic function, the amino group and the OH (SH) group of the alcohol (enethiol) function. The energy gap between the CS global minimum and the SB form decreases significantly on going from serine to cysteine. Hence, for the latter both CS and SB forms could coexist in the gas phase mainly at high temperatures. Anharmonicity effects are lower than 10%, and do not affect significantly the assignment of the fundamental vibrational modes. The calculated infrared spectra of the SB and CS forms of glycine-, serine-, and cysteine-Ca2+ complexes show very distinctive characteristics, which should permit to unambiguously characterize them by IR multiphoton dissociation (IRMPD) techniques. © 2011 Wiley Periodicals, Inc. Int J Quantum Chem, 2012

Calmodulin readily switches conformation upon protonating high pKa acidic residues.

Abstract: We investigate protonation as a possible route for triggering conformational change in proteins by focusing on the calmodulin (CaM) example. Two hundred nanosecond molecular dynamics (MD) simulations are performed on both the extended and compact forms of calcium loaded CaM. The stability of both structures is confirmed under prevailing conditions. Protonation of nine acidic residues with upshifted pK(a) values leads to a large conformational change in less than 100 ns. The structure attained is consistent with fluorescence resonance energy transfer experimental results as well as structures from an ensemble compatible with NMR data. Analysis of the MD trajectories summing up to one microsecond implies that the key events leading to the completion of the conformational change begins with an initial formation of a salt bridge between the N-lobe and the linker, followed by the bending of the C-lobe and the organization of a stabilizing hydrophobic patch between the lobes. We find that CaM utilizes its Ca2+ ions to harden/soften different regions so as to achieve various conformations. Thus, barrier crossing between extended and compact forms of CaM which is normally a rare event due to the repulsive electrostatic interactions between the two lobes is facilitated by protonation of high pK(a) residues. The results delineate how pH changes might be utilized in the cell to achieve different conformation-related functions.

A salt-bridge controlled by ligand binding modulates the hydrolysis reaction in a GH5 endoglucanase

Abstract: the unliganded wild-type structure. The structure of the enzyme solved in complex with a cleavage product (cellobiose) revealed ligand-induced conformational changes in the loop carrying Glu140 (proton donor). The reorientation of Glu140 in the complex reduces the separation of the catalytic glutamate residues to 4.3 A˚. In this study, we took advantage of conventional and steered molecular dynamics (MD) simulations along with in silico and in vitro mutagenesis to investigate the ligand-induced changes of the enzyme and interactions involved in preservation of Cel5B conformations in the presence and absence of substrate. We determined that the variation in separation of catalytic glutamates in the absence and presence of substrate is due to the different protonation states of the proton donor glutamate that is largely governed by conformational changes in the b3a3 loop. In the absence of substrate, the conformation of Cel5B is preserved by an electrostatic interaction between deprotonated Glu140 and protonated His91. The ion pair is interrupted upon the binding of substrate, and the positional displacement of the b3a3 loop allows Glu140 to become oriented within the active site in a less hydrophilic microenvironment that assists in Glu140 protonation.

Significant stabilization of ribonuclease A by additive effects

Abstract: Among the strategies that employ genetic engineering to stabilize proteins, the introduction of disulfide bonds has proven to be a very potential approach. As, however, the replacement of amino acid residues by cysteines and the subsequent formation of the covalent bond can result in a severe deformation of the parental protein structure, the stabilization effect is strongly context dependent. Alternatively, the introduction of charged amino acid residues at the surface, which may result in the formation of extra ionic interactions or hydrogen bonds, provide propitious means for protein stabilization. The generation of an extra disulfide bond between residues 4 and 118 in ribonuclease A had resulted in a stabilization by 6 °C or 7 kJ mol−1, which was mainly caused by a deceleration of the unfolding reaction [Pecher, P. & Arnold, U. (2009) Biophys Chem, 141, 21–28]. Here, Asp83 was replaced by Glu resulting in a comparable stabilization. Moreover, combination of both mutations led to an additive effect and the resulting ribonuclease A variant (Tm ∼ 76 °C, ΔG°∼ 53 kJ mol−1) is the most stable ribonuclease A variant described so far. The analysis of the crystal structure of A4C/D83E/V118C-ribonuclease A reveals the formation of a salt bridge between the γ-carboxyl group of Glu83 and the e-amino group of Lys104. Database Ribonuclease (EC3.1.27.5) Structured digital abstract • RNase A and RNase A bind by x-ray crystallography (View interaction)

Accurate Determination of pH by Use of Ionic Liquid Salt Bridge

Abstract: A salt bridge is a device indispensable in electrochemical measurement. Since the invention of that, a concentrated KCl solution has fulfilled the role over 100 years. The excellent performance of a concentrated KCl salt bridge (KClSB), however, does not always work satisfactory. The reason why a KClSB has been used for a long time is mainly the lock of better alternatives. It is anticipated that a newly proposed salt bridge based on moderately hydrophobic ionic liquids solves the intrinsic problems of a KClSB and bring a new dimension to not only pH measurement but also electroanalytical chemistry. In this paper, we introduce the fundamental property of an ionic liquid salt bridge and the application of it to pH measurements.

Reversible Covalent Bond Toolbox

Abstract: In supramolecular chemistry, functional group interactions play a critical role. The use of covalent interactions, however, is not as common as noncovalent interactions mostly because of their irreversible nature. This chapter covers those covalent interactions that are readily reversible and are often used in the construction of supramolecular assemblies and sensor design. Especially important in such work are boronic acid interactions with diols and other nucleophiles/Lewis bases, anion–metal interactions, and aldehyde–amine/alcohol interactions because of their ready reversibility. Keywords: reversible covalent bond; supramolecular assembly; sensor design; boronic acid; anion–metal interactions; aldehyde–amine/alcohol interactions