First Principle Calculation of Nuclear Magnetic Resonance (NMR) chemical shift Kanchan Sonkar Center...

First Principle Calculation of Nuclear Magnetic Resonance (NMR) chemical shift

Kanchan SonkarCenter of Biomedical Magnetic Resonance

SGPGIMS-Campus, Lucknow, India

05/04/23Asia 2 2011-Joint

CHAIN/EU-IndiaGrid2/EPIKH School for Application Portng

Overview

• Introduction to NMR spectroscopy• Membrane proteins • structure calculation• Problems associated• Application to be ported

05/04/23Asia 2 2011-Joint


Basic principle of NMR spectroscopy

• Relies on magnetic properties of nuclei, which behave like tiny bar magnets

Bo

05/04/23Asia 2 2011-Joint


Resonance frequency is directly proportional to– Gyromagnetic ratio– Applied magnetic field

At B=11.7 T (tesla, 104 Gauss) the resonant frequency for 1H is 500 MHz

05/04/23Asia 2 2011-Joint


NCH 15131 104

05/04/23Asia 2 2011-Joint


Other useful nuclei used in NMROther useful nuclei used in NMR

1H 1/2 99.98 1.00 1.00 100.0002H 1 1.5x10-2 9.65x10-3 1.45x10-6 15.35113C 1/2 1.108 1.59x10-2 1.76x10-4 25.14414N 1 99.63 1.01x10-3 1.01x10-3 7.22415N 1/2 0.37 1.04x10-3 3.85x10-6 10.13319F 1/2 100 0.83 0.83 94.07723Na 3/2 100 9.25x10-2 9.25x10-2 26.45131P 1/2 100 6.63x10-2 6.63x10-2 40.481113Cd 1/2 12.26 1.09x10-2 1.33x10-3 22.182

isotope I abundance(%) sensitivity (relative)

sensitivity (absolute)

Frequency (MHz) at 2.3488

05/04/23Asia 2 2011-Joint


Applications of NMR

• Three-dimensional structural studies– Proteins, Protein-ligand complexes– DNA, RNA, Protein/DNA complexes– Natural product chemistry– Synthetic organic chemistry

• Study of dynamic processes– reaction kinetics– study of equilibrium (chemical or structural)

• Drug Design• Medicine: MRI, Metabonomics

05/04/23Asia 2 2011-Joint


NMR spectrometer

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Spectrum acquisitionSpin in a magnetic field B0 Magnetization lies along z- axis

05/04/23Asia 2 2011-Joint


• rf pulse application on z-magnetization

Spectrum acquisition

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Spectrum acquisition• Relaxation process

– Transverse relaxation– Longitudinal relaxation

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• Signal recorded in the form of Free Induction Decay (FID)

FID (time domain signal) Spectrum (frequency domain signal)

05/04/23Asia 2 2011-Joint


Interpretation of NMR spectrum• Chemical shift– Nuclei resonate at different Larmor frequencies– Larmor frequency depends upon• Local environment• Presence of other magnetic nuclei

Shielding tensor

Chemical shift

05/04/23Asia 2 2011-Joint


Chemical shift can be calculated as

Some reference compounds:● 1H, 13C, 29Si → tetramethylsilane (TMS) ● 15N → liquid NH3● 17O → liquid H2O● 19F → liquid CFCl3● 27Al → AlCl3 in D2O● 43Ca → CaCl2(aq) 1 mol/L

05/04/23Asia 2 2011-Joint


Chemical shift range

1H

13C

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Chemical shift

• The origin of the chemical shift are the orbital currents induced by the external magnetic field

• Gives information of local environment

05/04/23Asia 2 2011-Joint


Solid state NMR• Molecules in liquids move very fast

– Giving sharp NMR lines (isotropic chemical shift)

• In solids– No movement is possible

• Hence, broad NMR peaks (anisotropy)• No averaging of spin interaction-broader lines

Poly crystalline line shape

05/04/23Asia 2 2011-Joint


• Averaging of spin interactions• Some interactions depend on – Magic angle spinning spin the sample at the magic

angle ~ 54.74°

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• Effect of Magic Angle Spinning on Glycine

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Proteins

• Most important biological molecule• Perform various functions

– Tissue regeneration– Immune responses for human body– Cellular signalling and molecular transport

• Specialized protein classes for various processes

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Membrane proteins• Most abundant proteins• Involve in almost all cellular processes

GPCR-richest receptor target for drug discovery

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Types • Peripheral membrane proteins• Integral membrane proteins

Spectrin

Accessory

Glycoprotein

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Integral membrane proteins

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Structure calculation methods

• X-ray crystallography– Protein must be in crystallized form

• Atomic force method– Provides only surface information

• Solution NMR– Unsuitable for membrane proteins

• Solid state NMR – Most promising techniques

05/04/23Asia 2 2011-Joint


Solid state NMR of membrane proteins

• Capable of determining the three-dimensional structures of proteins in their native functional environments

• 15N chemical shift and 15N–1H dipolar coupling gives the structural information

Pulse sequences for 2D PISEMA experiments

05/04/23Asia 2 2011-Joint


Protein Sci. 2003 12: 403-41105/04/23

Asia 2 2011-Joint CHAIN/EU-IndiaGrid2/EPIKH School for

Application Portng

J. Mol. Biol. (2004) 341, 869–879

Few examples representing PISEMA spectra

05/04/23Asia 2 2011-Joint


Problems associated

• Applicable for low molecular weight proteins• Solution:– Design new pulse sequences– Use of another naturally occurring isotope 13C

nuclei– Calculation of 13C chemical shift tensors in alpha-

helix and beta sheets

05/04/23Asia 2 2011-Joint


Application to be ported– Installation and compilation of Quantum Espresso– Running examples on GRID infrastructure– Calculation of 13C chemical shift for glycine and N-

Acetyl Valine– Requirements:• Scientific Linux• Quantum Espresso software• C and Fortran compilers• MPI-Libraries

05/04/23Asia 2 2011-Joint


First Principle Calculation of Nuclear Magnetic Resonance (NMR) chemical shift Kanchan Sonkar Center...

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