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Prof. Erik Lindahl Course - "Molecular Biophysics"

About this Course

This excellent Youtube course is taught by ** Erik Lindahl**, Professor of Biophysics department of Biochemistry & Biophysics at Stockholm University

** Youtube Channel**: Link

** Duration**: ~20 hours

** Contents**: Bioinformatics, structural bioinformatics, protein folding, thermodynamics, molecular mechanics, molecular dynamics, drug design, molecular docking, free energy etc...

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