Prof. Erik Lindahl Course - "Molecular Biophysics"¶
Table of Contents¶
Links | Topics | Youtube Links |
---|---|---|
Lecture 1 | DNA, RNA, proteins, the genetic code ... | link |
Lecture 2 | molecular interactions, energy, force field... | link |
Lecture 3 | amino acid flexibility, thermodynamics, entropy, free energy,... | link |
Lecture 4 | H-bond, the hydrophobic effect, packing, protein folding,... | link |
Lecture 5 | amino acid properties and structure,... | link |
Lecture 6 | simulation, molecular dynamics, molecular mechanics, minimisation,... | link |
Lecture 7 | Fibrous, globular, and membrane proteins,... | link |
Lecture 8 | lipid bilayer, cellular membranes,... | link |
Lecture 9 | fold, protein similarity, evolution, classification, database,... | link |
Lecture 10 | phase transition, protein folding, kinetics of folding,... | link |
Lecture 11 | bioinformatics, from DNA to protein, homologs, phylogenetic trees, RMSD | link |
Lecture 12 | drug target, binding sites, ligand binding, affinity, discovery process | link |
Lecture 13 | binding free energy, computational design of protein folds | link |
Lecture 1¶
Topics | Duration (~1:15:00) | Youtube Links |
---|---|---|
Class introduction: From life to molecular biophysics | 21:48 | link |
1 - The special properties of water | 4:45 | link |
2 - From data and models to DNA structure | 3:53 | link |
3 - The components of DNA | 2:28 | link |
4 - Chargaff's ratio - Watson & Crick's key to DNA structure | 3:10 | link |
5 - Base stacking stabilizes DNA | 1:41 | link |
6 - Watson-Crick base pairing | 0:36 | link |
7 - Information contents in DNA | 2:10 | link |
8 - Size of genomes in bases & protein genes | 2:01 | link |
9 - RNA structure | 2:28 | link |
10 - Three forms of RNA - mRNA | 3:57 | link |
11 - Three forms of RNA - rRNA & tRNA | 1:17 | link |
12 - The central dogma of molecular biology | 1:26 | link |
13 - Replication | 1:39 | link |
14 - Transcription | 1:03 | link |
15 - Translation | 2:15 | link |
16 - The genetic code | 2:49 | link |
17 - Structure of proteins | 4:03 | link |
18 - Protein structure determination - X-ray crystallography & Cryo-EM | 7:26 | link |
19 - Proteins are polypeptides of amino acids | 3:45 | link |
Reading suggestions & study questions | 2:20 | link |
Lecture 2¶
Topics | Duration (~1:22:00) | Youtube Links |
---|---|---|
1 - Modeling molecules with computers | 3:16 | link |
2 - Molecular interactions are due to electrons | 5:32 | link |
3 - Induced dipole-dipole interactions | 7:18 | link |
4- Do we need quantum chemistry here | 3:17 | link |
5 - Semi-empiric interaction models | 4:29 | link |
6 - Bonds and approximating potentials | 6:40 | link |
7 - Energy units | 2:50 | link |
8 - Angles | 1:56 | link |
9 - Torsions or dihedrals | 4:07 | link |
10 - Periodic torsion potentials | 4:51 | link |
11 - Phi/psi torsions, Ramachandran diagrams | 4:45 | link |
12 - Nonbonded interactions and their strengths | 5:35 | link |
13 - Partial charges on atoms in molecules | 2:46 | link |
14 - Van der Waals interaction forms: Buckingham & Lennard-Jones | 5:54 | link |
15 - A complete potential function | 4:12 | link |
16 - Hydrogen bonds - orbitals, donors and acceptor | 4:57 | link |
17 - Hydrogen bonds stabilise biomolecules | 4:38 | link |
18 - H-bonds in folding & Energy landscapes | 9:18 | link |
19 - Study questions | 0:48 | link |
Lecture 3¶
Topics | Duration (~1:11:00) | Youtube Links |
---|---|---|
1 - Interactions and their role for flexibility in amino acids | 2:18 | link |
2 - Peaks & valleys in energy landscapes | 0:52 | link |
3 - The Maxwell-Boltzmann velocity distribution | 2:41 | link |
4- Deriving the Boltzmann distribution (a special case) | 8:58 | link |
5 - Relative populations in states | 5:47 | link |
6 - Entropy and free energy - accounting for multiplicity/volume | 9:32 | link |
7 - Microstates vs. Macrostates (multiplicity vs. disorder) | 6:25 | link |
8 - The hydrophobic effect is entropic in nature | 0:39 | link |
9 - The laws of thermodynamics | 2:54 | link |
10 - Helmholtz vs. Gibbs free energy | 5:22 | link |
11 - The thermodynamic definition of temperature | 5:07 | link |
12 - Phase transitions from entropy-enthalpy balance | 4:04 | link |
13 - Polywater - learn to reason using free energy | 6:26 | link |
14 - The multiple ice phases of water | 1:35 | link |
15 - Hydrogen bond formation in water interpreted with entropy/enthalpy | 6:52 | link |
16 - Study questions | 0:49 | link |
Lecture 4¶
Topics | Duration (~1:28:00) | Youtube Links |
---|---|---|
1 - Hydrogen bond formation in a protein | 4:37 | link |
2 - Calculating free energies from experiments | 3:17 | link |
3 - Solving for S and H from G | 4:21 | link |
4 - Comparing G, H & S for liquid vs. aqueous phase | 3:47 | link |
5 - The hydrophobic effect | 4:42 | link |
6 - Temperature dependence of the hydrophobic effect | 3:21 | link |
7 - Packing is simple once phases have separated | 2:28 | link |
8 - Protein folding is initially a hydrophobic collapse | 2:02 | link |
9 - Enthalpy and entropy in energy landscapes | 3:38 | link |
10 - Populations and transitions in energy landscapes | 1:06 | link |
11 - Statistical mechanics connects microstates to macrostates | 0:45 | link |
12 - Deriving the Boltzmann distribution - general case | 12:06 | link |
13 - The partition function | 3:46 | link |
14 - Entropy of systems / states - Shannon entropy | 9:03 | link |
15 - Entropy vs. energy describes stability of systems | 3:09 | link |
16 - Understanding (phase) transitions from S(E) | 6:46 | link |
17 - Kinetics of transitions is governed by energy barriers | 8:30 | link |
18 - Introduction to stability in the alpha helix | 2:17 | link |
19 - Introduction to stability in the beta sheet | 1:46 | link |
20 - Electrostatics inside proteins | 3:37 | link |
21 - Alpha helix capping with charges | 3:40 | link |
22 - Study questions | 1:02 | link |
Lecture 5¶
Topics | Duration (~1:33:00) | Youtube Links |
---|---|---|
1 - Amino acids are chiral zwitterions | 4:31 | link |
2 - Amino acid classifications & protein size diversity | 3:10 | link |
3 - Anfinsen's dogma (the thermodynamic hypothesis) | 2:41 | link |
4 - Torsions in amino acids - phi, psi, omega, chi | 4:45 | link |
5 - Levinthal's paradox | 3:16 | link |
6 - Primary to quaternary structure | 1:56 | link |
7 - Helices & sheets in proteins | 2:12 | link |
8 - The alpha helix is right-handed due to L amino acids | 1:35 | link |
9 - Specific properties of amino acid side chains | 1:47 | link |
10 - Alanine & glycine are small & simple side chains | 2:25 | link |
11 - Larger & hydrophobic side chains | 0:56 | link |
12 - Tryptophan is a big & bulky side chain | 4:23 | link |
13 - Cysteine can form disulfide bridges | 4:04 | link |
14 - Proline has a ring and breaks helices | 1:18 | link |
15 - Alpha, 3_10 and pi helices | 2:38 | link |
16 - Helix packing - ridges and valleys | 2:15 | link |
17 - Free energy of alpha helix formation | 7:52 | link |
18 - The helix-coil transition | 4:13 | link |
19 - The alpha helix initiation barrier | 5:17 | link |
20 - Kinetics of alpha helix formation | 2:59 | link |
21 - Sheets are antiparallel or parallel, and can have hydrophobic moment | 3:19 | link |
22 - Beta sheet stability and initiation barrier | 9:24 | link |
23 - Kinetics of beta sheet formation | 3:47 | link |
24 - The slow beta sheet formation can explain misfolding - prions | 6:51 | link |
25 - Properties (size) of the coil | 6:44 | link |
26 - Study questions | 0:39 | link |
Lecture 6¶
Topics | Duration (~1:41:00) | Youtube Links |
---|---|---|
1 - From static structures to simulations | 2:31 | link |
2 - Molecular dynamics as prediction of motion - challenges | 3:33 | link |
3 - Molecular dynamics as sampling is a more sound approach | 8:23 | link |
4 - Molecular dynamics simulations of real proteins | 2:04 | link |
5 - Don't mistake models for reality | 1:49 | link |
6 - Molecular dynamics compared to experiments - different strengths | 3:10 | link |
7 - Timescales in experiments and simulations | 3:21 | link |
8 - Molecular mechanics uses semi-empiric models | 3:04 | link |
9 - Integration using the leap-frog algorithm updates x & v | 6:15 | link |
10 - Flowchart of a typical simulation - femtosecond steps | 3:08 | link |
11 - Small fractions of states can still approximate the partition function well | 4:14 | link |
12 - Simulation ensembles (NVE, NVT, NPT) define what properties are constant | 7:48 | link |
13 - Examples of systems & timescales to target | 3:58 | link |
14 - Biomolecules need to be solvated (e.g. in water) | 2:20 | link |
15 - Periodic boundary conditions | 5:30 | link |
16 - Energy minimisation avoids clashes, which avoids crashes | 4:31 | link |
17 - The contents of a PDB structure file | 2:33 | link |
18 - Example biological problems we can target | 7:09 | link |
19 - Markov state models - slow processes from many short simulations | 2:30 | link |
20 - Potential of mean force - free energy along a reaction coordinate | 4:35 | link |
21 - Calculating binding free energy - alchemical transformation | 4:49 | link |
22 - Binding free energy - the free energy cycle & DDG values | 7:05 | link |
23 - Common simulation & visualisation tools | 6:40 | link |
24 - Study questions | 0:40 | link |
Lecture 7¶
Topics | Duration (~2:00:00) | Youtube Links |
---|---|---|
1 - Fibrous, globular and membrane proteins - the building blocks of life | 3:13 | link |
2 - Fibrous proteins are large building blocks that can reach macroscopic size | 6:03 | link |
3 - Collagen is a special proline helix (bone, teeth, parts of skin) | 5:50 | link |
4 - Elastin is a polymer with lysine links (blood vessels) | 5:17 | link |
5 - Coiled-coil helices form extended structures (e.g. myosin in muscles) | 7:41 | link |
6 - Leucine zippers & disulfide bridges stabilise coiled coils | 2:17 | link |
7 - Alpha-keratin (hair, wool, etc.) | 4:09 | link |
8 - Non-biological fibrous structures can sometimes be modified with proteins | 2:48 | link |
9 - Globular proteins are soluble in water | 2:45 | link |
10 - All-beta-sheet globular proteins | 7:13 | link |
11 - Packing of beta sheets - orthogonal/aligned strands, and beta meanders | 3:19 | link |
12 - Immunoglobulin fold - example of aligned beta strands | 2:33 | link |
13 - Gamma crystallin has more complex loops | 1:55 | link |
14 - The Greek Key supersecondary structure motif | 4:05 | link |
15 - Most sheets are meanders or Greek Keys, but there are exceptions | 3:50 | link |
16 - Beta sheets can drive oligomerization (multiuser formation) | 4:21 | link |
17 - All-alpha-helical globular proteins are diverse in structure | 1:39 | link |
18 - Four-helix bundles - examples of simple alpha helix structures | 1:20 | link |
19 - Cytochrome C | 2:45 | link |
20 - The tobacco mosaic virus coat protein | 3:38 | link |
21 - Hemerythrin | 2:54 | link |
22 - Design of four-helix bundles | 6:20 | link |
23 - The globin fold - hemoglobin & myoglobin | 9:00 | link |
24 - Mixed helix/sheet - alternating (a/b) or separated (a+b) elements | 1:08 | link |
25 - a/b folds - The TIM barrel | 4:59 | link |
26 - The Rossman fold - one sheet surrounded by helices | 4:11 | link |
27 - Parallel vs. antiparallel sheets are correlated with a/b vs. a+b | 1:34 | link |
28 - DNA-binding a+b structures - zinc finger & TATA-binding protein | 2:37 | link |
29 - Disordered protein structures (think function) | 2:19 | link |
30 - A thousand folds for the molecular biologist | 5:48 | link |
31 - Study questions | 1:23 | link |
Lecture 8¶
Topics | Duration (~1:50:00) | Youtube Links |
---|---|---|
1 - The internal structure of the lipid bilayer | 3:09 | link |
2 - Lipids are amphiphatic, often zwitterions, and aggregate into bilayers | 7:06 | link |
3 - The internal structure of the lipid bilayer | 8:12 | link |
4 - The fluid mosaic model of cellular membranes | 3:27 | link |
5 - Membrane proteins were crystallized by solubilisation in detergent | 3:52 | link |
6 - The first membrane protein structure - bacteriorhodopsin | 1:54 | link |
7 - Interactions between membrane proteins and lipids | 3:12 | link |
8 - Membrane proteins insert through the translocon | 6:09 | link |
9 - Membrane protein helix packing & the GXXXG motif | 3:15 | link |
10 - Membrane protein topology - the von Heijne "positive inside" rule | 4:10 | link |
11 - Membrane transport - passive vs. active & non-mediated vs. mediated | 6:03 | link |
12 - Ion channels | 4:23 | link |
13 - The KcsA bacterial K+ ion channel | 6:17 | link |
14 - The Kv voltage-gated K+ ion channel(s) in vertebrates | 7:00 | link |
15 - The aquaporin water channel | 2:21 | link |
16 - Ligand-gated ion channels mediate signals in the nervous system | 6:52 | link |
17 - The NKA (Na/K ATPase) pump maintains the ion imbalance by using ATP | 8:49 | link |
18 - Signaling - G-protein coupled receptors (GPCRs) | 5:13 | link |
19 - Signaling - Receptor Tyrosine Kinases (RTKs) | 4:26 | link |
20 - Viral fusion membrane proteins | 9:34 | link |
21 - Lipid Nanoparticles (LNPs) for mRNA vaccine delivery | 2:51 | link |
22 - Study questions | 1:06 | link |
Lecture 9¶
Topics | Duration (~1:48:00) | Youtube Links |
---|---|---|
1 - Most sequences end up in a small fraction of folds | 3:34 | link |
2 - Why are proteins similar - evolution or physics? | 3:22 | link |
3 - Classification of protein folds | 1:16 | link |
4 - Fold databases - CATH | 2:32 | link |
5 - Fold databases - SCOP | 3:27 | link |
6 - Evolution of protein structures - hemoglobin | 4:14 | link |
7 - Bacterial vs. eukaryotic/vertebrate proteins | 2:30 | link |
8 - Evolution can happen fast - tomcod PCB resistance | 2:53 | link |
9 - What features make for stable folds? | 2:05 | link |
10 - Most folds consist of 2-4 layers | 4:17 | link |
11 - Patterns we see occur because the are stable and avoid defects | 2:00 | link |
12 - Even small defects can destabilize an entire fold | 2:58 | link |
13 - The multitude principle - Common folds can accept many sequences | 0:46 | link |
14 - Sizes of helices/sheets are limited due to sequence pattern probabilities | 12:23 | link |
15 - Recap - secondary structure elements can't be too small or large | 1:08 | link |
16 - Small defects are bad because much fewer sequences will fit the fold | 5:13 | link |
17 - Stability distribution comes from interaction randomness, not Boltzmann | 11:05 | link |
18 - Most random sequences will not fold into proteins | 4:38 | link |
19 - It is rarer with helices than sheets inside proteins | 2:51 | link |
20 - Green Fluorescent Protein (GFP) | 3:19 | link |
21 - Conformational transitions - induced & selected fit | 3:35 | link |
22 - The allosteric transition of hemoglobin is critical for O2 transport | 2:33 | link |
23 - CD spectroscopy is useful to study unfolding | 4:36 | link |
24 - Folding of small domains is an all-or-none transition | 15:37 | link |
25 - Proteins will unfold at either high or low temperature | 4:51 | link |
26 - Study questions | 0:10 | link |
Lecture 10¶
Topics | Duration (~1:30:00) | Youtube Links |
---|---|---|
1 - Denaturation into molten globule or all the way to coil | 3:47 | link |
2 - Properties of real molten globules | 5:20 | link |
3 - Clouds of particles collapse into a phase transition, but not polymers! | 13:29 | link |
4 - Proteins are heteropolymers - side chain packing leads to phase transition | 4:12 | link |
5 - E & S decrease in balance during folding, but create a free energy barrier | 3:34 | link |
6 - Proteins have an energy gap to a single most-stable native state | 5:02 | link |
7 - Some proteins get help from chaperonins to fold, but how can others fold? | 3:16 | link |
8 - Potential models of protein folding to explain Levinthal's paradox | 0:48 | link |
9 - The diffusion-collision model - secondary structures form first | 2:58 | link |
10 - The hydrophobic collapse model - secondary structure forming at the end | 1:21 | link |
11 - The nucleation-condensation model - residues gradually expanding a core | 2:16 | link |
12 - Kinetics of protein folding and unfolding | 3:53 | link |
13 - Arrhenius plots reveal relative E for unfolded, transition and folded states | 6:43 | link |
14 - Obtaining S for unfolded, transition and folded states (like Arrhenius) | 2:11 | link |
15 - Folding barrier is entropy, unfolding is enthalpy | 2:10 | link |
16 - Apparent rates (approach to equilibrium) are easier to measure | 3:40 | link |
17 - Chevron plots reveal molecular details of folding & unfolding | 6:07 | link |
18 - Phi-value analysis from Chevron plots identifies transition state residues | 3:30 | link |
19 - Protein folding slows down when misfolded states become too stable | 3:09 | link |
20 - Proteins need both thermodynamic stability and fast folding pathways | 1:38 | link |
21 - The nucleation-condensation transition state explains Levinthal's paradox | 7:50 | link |
22 - Life is essentially physics & information | 4:42 | link |
23 - Study questions | 0:17 | link |
Lecture 11¶
Topics | Duration (~1:53:00) | Youtube Links |
---|---|---|
1 - : Bioinformatics focuses on evolution and data | 2:16 | link |
2 - Obtaining DNA from samples - Polymerase Chain Reaction (PCR) | 5:42 | link |
3 - Detection of nucleic acids & SNPs with molecular beacons and microarrays | 4:10 | link |
4 - Example of genetic tests for disease - BRCA | 2:04 | link |
5 - Chain termination (Sanger) sequencing | 5:04 | link |
6 - Shotgun sequencing | 4:24 | link |
7 - Sequencing produces more and cheaper data than any other scientific method | 6:28 | link |
8 - From DNA to proteins - open reading frames | 3:27 | link |
9 - Single-site vs. recombinant mutations | 3:06 | link |
10 - Homologs, orthologs & paralogs | 3:53 | link |
11 - Detecting relationship from similarity - dot plots | 2:13 | link |
12 - Amino acid sequence is more conserved than DNA | 1:13 | link |
13 - The extreme growth of biological sequence & structure databases | 3:02 | link |
14 - Protein sequence similarity: From mutation probabilities to scoring matrices | 7:29 | link |
15 - Phylogenetic trees | 6:11 | link |
16 - Sequencing will rapidly & cheaply tell us where structures mutate - variants | 2:03 | link |
17 - Protein structure RMSD vs. sequence identity | 7:57 | link |
18 - E-values indicate how statistically significant matches are | 4:15 | link |
19 - Position-specific scoring matrices add more biological information | 5:42 | link |
20 - Hard predictions are turning easy, impossible ones are becoming tractable | 2:23 | link |
21 - Secondary structure prediction | 3:03 | link |
22 - Homology modeling | 3:20 | link |
23 - Homology modeling depends on good alignments and databases - use web servers | 2:27 | link |
24 - Fragment-based ab initio prediction with ROSETTA | 6:03 | link |
25 - Co-evolution (correlated mutations) improves ab initio prediction | 4:45 | link |
26 - Deep learning ab initio prediction of protein structure with Alphafold | 7:45 | link |
Study questions | 1:32 | link |
Lecture 12¶
Topics | Duration (~1:41:00) | Youtube Links |
---|---|---|
1 - Discover drugs by targeting proteins | 3:10 | link |
2 - Understand your drug target - SARS-CoV-2 as an example | 7:19 | link |
3 - From biology to target proteins to binding sites | 2:03 | link |
4 - Ligand bind into pockets of receptors | 1:46 | link |
5 - Membrane proteins are some of the most common drug targets | 1:25 | link |
6 - Affinity vs. efficacy & agonists vs. antagonists vs. inverse agonists | 6:08 | link |
7 - ADME / Tox | 6:12 | link |
8 - Lipinski's rule(s) of 5 | 7:22 | link |
9 - Fantastic drugs and where to find them | 3:06 | link |
10 - Steps in the drug discovery process | 6:04 | link |
11 - From preclinical through phase I, II, & III trials to regulatory approval | 6:37 | link |
12 - The omeprazole drug was carefully optimised and made billions for Astra | 2:09 | link |
13 - Hit identification | 3:26 | link |
14 - Experimental high-throughput screening to test 500,000 molecules | 3:34 | link |
15 - Quantitative structure-activity relationship (QSAR) tries to predict drugs | 4:29 | link |
16 - A pharmacophore is a profile of a drug's average properties | 1:53 | link |
17 - An example pharmacophore | 2:38 | link |
18 - Docking is virtual (computational) high-throughput screening | 4:03 | link |
19 - Docking methods - find best ways to put two molecules together | 3:35 | link |
20 - Docking has limited accuracy, but achieves extreme throughput | 5:32 | link |
21 - Fragment-based drug design tries to build a drug into a pocket | 1:45 | link |
22 - Docking scoring functions can be physical, empirical, or knowledge-based | 3:29 | link |
23 - Knowledge-based (statistical) scoring on a grid is very fast | 0:43 | link |
24 - Allowing ligand flexibility and producing a final ranked list | 1:48 | link |
25 - Experimental vs. virtual (docking) high-throughput screening | 1:26 | link |
26 - Docking quality depends on the input structure or homology model quality | 2:50 | link |
27 - Validation with experimental co-crystal structure determination | 2:17 | link |
28 - Improving affinity - lead optimization | 2:35 | link |
29 - Lead optimization for the HIV-1 protease inhibitor | 3:16 | link |
Study questions | 0:47 | link |
Lecture 13¶
Topics | Duration (~1:41:00) | Youtube Links |
---|---|---|
1 - Free energy calculation provides good relative binding free energies | 4:31 | link |
2 - Full simulations of binding reveal kinetics & barriers | 5:11 | link |
3 - Designing a helix to selectively bind a membrane protein | 4:36 | link |
4 - Strengths/weaknesses of protein/peptide drugs (biologicals) | 3:46 | link |
5 - Liraglutide - a biological used to treat type-II diabetes | 3:04 | link |
6 - Allosteric modulation of igand-gated ion channels with different drugs | 3:33 | link |
7 - Poly-unsaturated fatty acids (PUFAs) can rescue mutated voltage sensors | 5:34 | link |
8 - disaster in phase I trials for a new biological - TGN1412 | 4:28 | link |
9 - Computational design of new protein folds | 6:36 | link |
10 - Study questions | 0:27 | link |
11 - Finishing up - recap of lecture themes | 4:25 | link |