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Ion Exchange01:17

Ion Exchange

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Ion exchange chromatography separates charged molecules from a solution by reversibly exchanging them with mobile, or 'active', ions associated with the oppositely charged stationary phase. This method can be used to separate ions, soften and deionize water, and purify solutions. The polymers comprising the ion-exchange column are high-molecular-weight and chemically stable polymers, crosslinked to be porous and essentially insoluble. They are also functionalized with either acidic or...
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¹H NMR of Conformationally Flexible Molecules: Temporal Resolution00:52

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At room temperature, the chair conformer of cyclohexane undergoes rapid ring flipping between two equivalent chair conformers at a rate of approximately 105 times per second. These two chair conformers are in equilibrium. The rapid ring flipping results in the interconversion of the axial proton to an equatorial proton and an equatorial to the axial proton. Such interconversions are too rapid and cannot be detected on the NMR timescale. Hence, the NMR spectrometer cannot distinguish between the...
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Acids are classified by the number of protons per molecule that they can give up in a reaction. Acids such as HCl, HNO3, and HCN that contain one ionizable hydrogen atom in each molecule are called monoprotic acids. Their reactions with water are:
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Chemical Shift: Internal References and Solvent Effects01:17

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In an NMR sample, precise measurement of the absolute absorption frequencies of nuclei is difficult. A standard internal reference compound is added, and the frequency difference between the reference signal and sample signals is measured.
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Extraction: Effects of pH00:53

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Consider a neutral form of an amine, B, with a partition coefficient, K, in a liquid mixture containing organic and aqueous phases. The pH of the aqueous phase affects the charge on acidic and basic solutes, and the charged form is usually more soluble in the aqueous phase. Suppose the conjugate acid form of the amine is soluble only in the aqueous phase while the base form is soluble in both phases. Then the distribution coefficient, D, can be given as the ratio of amine concentration in the...
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¹H NMR of Labile Protons: Deuterium (²H) Substitution00:48

¹H NMR of Labile Protons: Deuterium (²H) Substitution

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This lesson illustrates the role of deuterium substitution in simplifying the NMR spectrum of compounds comprising labile protons. One method employed is the use of deuterium. Amongst the three isotopes of hydrogen, deuterium (2H) has a nucleus composed of one proton and one neutron. When the D2O solvent is added to a pure dry ethanol solution, its labile proton is substituted with deuterium.
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Constant pH Replica Exchange Molecular Dynamics in Explicit Solvent Using Discrete Protonation States:

Jason M Swails1, Darrin M York2, Adrian E Roitberg1

  • 1Quantum Theory Project, Chemistry Department, University of Florida , Gainesville, Florida 32611, United States.

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Constant pH molecular dynamics simulations (CpHMD) in implicit solvent yield poor pKa predictions. A new explicit solvent method with protonation state changes and replica exchange improves pKa accuracy for biomolecules.

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Area of Science:

  • Computational chemistry
  • Biomolecular simulations
  • Biophysics

Background:

  • Constant pH molecular dynamics (CpHMD) in implicit solvent often fails to accurately predict pKa values due to sampling unrealistic conformations.
  • Generalized Born (GB) implicit solvent models can limit the accuracy of pKa predictions in long-timescale simulations.

Purpose of the Study:

  • To develop and validate a novel method for accurate pKa prediction using CpHMD in explicit solvent.
  • To improve the sampling of relevant protonation states and conformations for biomolecules.

Main Methods:

  • A hybrid approach combining standard molecular dynamics (MD) in explicit solvent with protonation state changes attempted in GB implicit solvent at fixed intervals.
  • Utilizing replica exchange along the pH-dimension (pH-REMD) to enhance sampling of titration behavior.
  • Analyzing the impact of simulation parameters like unit cell size and relaxation dynamics on titration curves.

Main Results:

  • The proposed explicit solvent CpHMD method, enhanced with pH-REMD, yields improved pKa predictions compared to implicit solvent methods.
  • Accurate pKa values were obtained for hen egg white lysozyme (HEWL) over hundreds of nanoseconds of simulation.
  • The method was successfully tested on amino acid model compounds and a pentapeptide.

Conclusions:

  • The developed explicit solvent CpHMD method with pH-REMD offers a more reliable approach for predicting pKa values of biomolecules.
  • This method overcomes limitations of implicit solvent models by enabling more realistic conformational sampling.