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Summary Biophysics and Bioengineering for Pharmaceutical Sciences (2021)

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  • Course
  • Biophysics and Bioengineering for Pharmaceutical Sciences (4323LSBBP)
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  • Universiteit Leiden (UL)

Summary of all BBps lectures (2021). Detailed information about 'Biosensors' and 'Label-free biosensing techniques' (page 8) is missing. My grade: 10.

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Document information

  • September 16, 2021
  • 21
  • 2020/2021
  • Class notes
  • Dr. a. mashaghi
  • All classes

Subjects

  • biophysics
  • bioengineering
  • leiden
  • bbps
  • pharmaceutical sciences
  • leiden universiteit
  • leiden university
  • universiteit leiden
  • biophysics and bioengineering
  • biophysics and bioengineering for pharmaceutical s

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  • Universiteit Leiden (UL)
  • BioPharmaceutical Sciences MSc
  • Biophysics and Bioengineering for Pharmaceutical Sciences (4323LSBBP)
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Biophysics and Bioengineering for Pharmaceutical Sciences
Introduction to Biophysics and Bioengineering
Biophysics = branch of science concerned with the application of physical principles and methods to biological problems
 1892 – Karl Pearson introduced the term (“biophysics not improbably has an important future”)
Physics = a science that deals with matter and energy and their interactions - generic principles that control nature
Drug = a substance used to treat dysfunctional human body (and other biological organisms)
 Proteins = primary functional elements in human body  drug has to target protein to correct for a dysfunction
 Protein = matter drug = matter drug interacts with proteins (matter with matter - = physics)
Birth of biophysics: finding protein structure (Kendrew & Perutz – first to defined structure of protein)
You need to know the structure of a protein in order to be able to design a drug for it
Biophysics fields: cell biophysics, biophotonics, structural biology, biomechanics, molecular biophysics, theoretical biophysics,
systems biophysics, nanobiophysics
Bioengineering = the application of engineering principles, practices and technologies to the fields of medicine and biology
Engineering = the application of science and mathematics by which the properties of matter an the sources of energy in nature
are made useful to people | = the branches of science and technology concerned with the design, building and use of
engines, machines and structures
Engineering vs. Science:
- Creating new things or processes using existing knowledge - Creating knowledge
- Need/application driven - Hypothesis driven
- Results are expected to be implemented - Results are expected to be published
Bioengineering field: biomaterials, bioinformatics, medical imaging & bio-optics, rehabilitation engineering, cell & tissue
engineering, bioinstrumentation, biomechanics, biotransport & drug delivery, genetic engineering, biosensors & electronics,
neural engineering, bionanotechnology
Biophysics and bioengineering are growing fields (bioengineering rose after biophysics had become a thing)
Donald Ingber: organ-on-chip | David Weitz: microfluidics | Bob Langer: nanoparticle technology | Alexander van
Oudenaarden: application of biophysics to medical problems | Uri: theoretical biophysics, systems biology
Initiatives: Wyss institute – for organ-on-chip | Max Planck – for physics and medicine
Physics for pharmacy ≠ medical physics
 Medical physics: CT-scan, MRI – instruments for diagnostics
 Use physics to understand a system and then use understanding to develop drug
Consortium ATOM was created to address challenges in pharmaceutical sciences
Eroom’s law = cost of developing a drug is high and increasing – time to develop is long, much money needed, start with many
drugs and most of them fail  new innovative approaches needed  use physics and engineering

Molecular Biophysics for Pharmaceutical Sciences
Molecular biophysics: I. Structural biology (bulk analysis) II. Single-molecule biophysics (single molecule)
Structural biology = a branch of biophysics concerned with the molecular structure of biological macromolecules, especially
proteins and nucleic acids
 Importance: function of biological macromolecules is intricately related to their 3D shape & structure
Molecule structure - protein:
 Primary – sequence (which amino acids in what order?)
 Secondary – local folding (α-helix, β-sheet)
 Tertiary – long-range folding (how chain folds like a rope)
 Quaternary – multimeric organization (when multiple proteins come together to form a complex, e.g. ribosome)
 Supramolecular – large size assemblies
Watson & Crick – structure of DNA | Perutz & Kendrew – first structure of protein | Pauling – α-helix | Rosalind Franklin
– X-ray diffraction of DNA (α-helix experimentally) | Dorothy Hodgkin – structure of B12/insulin
Tertiary protein structure: protein folding  3 approaches to measure protein folding
1. Experimental determination (X-ray crystallography, NMR)
2. Comparative modeling based on homology - compare unknown with known structure if sequences are similar
3. Ab initio (de novo) prediction - make model of polymer that moves & with interactions  find minimum energy / in
time find structure that is energetically & entropically best (Molecular Dynamics simulation)
X-ray crystallography: used to determine 80% of structures
- Requires: high protein concentration, crystals (pure protein needed to get crystals) - impurity = no crystallization
- Solubilization of the over-expressed protein
- Structure determination by diffraction of protein crystals
- Size of molecule: no theoretical limit
 Crystals act as a 3D grating & produce diffraction  diffraction pattern contains complete info on placement of
scatterers (= electrons in atoms)
 By Fourier transforming the diffraction pattern, we obtain info on the structure of the molecule in the crystals

, Nuclear Magnetic Resonance (NMR):
- Magnetic field applied to proteins in solution
- Does not require crystallization
- Solubilization of the over-expressed protein (must be soluble)
- Structure determination of a molecule as it exists in solution
- Size-limit is a major factor
 PROs: high resolution info | does not require a protein crystal & not affected by crystal contacts | can be used to
study flexible /dynamic proteins | reflects conformational averaging
 CONs: requires high conc of soluble protein (to generate signal, because not super sensitive) | cannot be applied to
large proteins (800kDa max) | cannot be used with amyloid fibrils (not soluble)
 Measures nuclear magnetism or changes in nuclear magnetism in a molecule
 NMR spectroscopy measures the absorption of light (radio waves) due to changes in nuclear spin orientation
 Light = electromagnetic wave (when you apply light to sth, you apply a magnet to it)
 NMR only occurs when a sample is in a strong magnetic field
 Different nuclei absorb at different energies (frequencies)
 Atom has spin = nucleus of atom acts like little magnet  interacts with external magnet (H1, C13)
 Not all atoms have this magnetic property (spin) - C 12 does not, but its isotope C13 does
 Spin interacts with externally applied magnetic field  spin orients towards certain direction  at a specific
frequency an additional oscillating magnet can interact with the spin H 1 or C13 atoms  absorption of energy by
system that depends on environment (neighborhood) of atom of interest (e.g. everything around specific H atom
affects interaction)  because of this you can learn about the neighborhood of atom & by putting neighborhoods
together, about the structure of the protein
 Spin interacts with neighborhood through J-coupling or chemical shift
 Molecules in solution rotate very fast  many signals: average out  simplifies equation of interactions (equation
becomes linear if proteins rotate fast)  interpretable  extract structure of protein from equation
 The larger the protein gets, the slower it rotates  complex equation (not linear)  data not interpretable
Disadvantages:
o X-ray crystallography: producing enough protein for trials | crystallization time & effort (& difficult)
o NMR: producing enough labeled (H 1, C13) protein for collection | size of protein | assignment process is slow & error
prone
Bulk measurements: average of measured quantity is obtained  by averaging you may lose information!
Single molecule measurement: distribution of measured quantity is obtained (e.g. different points in cell cycle)
 Signal of 1 molecule is very weak (close to noise)  difficult to measure signal
 Put single-molecule measurements together to get same result as with bulk measurement (no info lost)
An individual enzyme may exist in ≥ 2 states of activity that are not revealed by bulk studies (e.g. speed of RNA polymerase
transcription)
 Static heterogeneity = different enzyme molecules function at different rates (e.g. a lame popu & a fast popu)
 Dynamic heterogeneity = a given single enzyme can switch between different rates
If we have heterogeneity in a dynamic system and heterogeneity is important  use single-molecule analysis
If we want to get an average idea of dynamic system  use bulk analysis
Single-molecule techniques:
1. Atomic Force Microscopy (AFM)
2. Laser traps (optical tweezers)
3. Single molecule fluorescence
Atomic Force Microscopy (AFM) ------for single-molecule
imaging------------------------->
- ‘feels’ surface of sample with tip of the cantilever by touching & moving over
sample with cantilever tip to understand what object is
- When cantilever tip touches surface, cantilever bends  (laser) light that shines on back of cantilever and goes to mirror,
will move, because angle will change  detected by photodetector
 Tilted light (object touched) can be seen with computer
 Angle of light (shining on back of cantilever) only changes when cantilever tip touches sample  light location
changes  surface is reached
 When surface is reached, don’t move to much, because this can break tip or sample  go backwards & start
scanning surface
 When object on surface is reached, cantilever bumps into it  cantilever will go above object (if cantilever is soft
enough) & touch surface of molecule
- Sample in liquid (substrate) for biology
- Can be done on: single molecule & cell
- Resolution depends on size of cantilever tip (50 µm, 10µm, 10 nm, etc.)

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