Protein structure:

Angles in the protein backbone

spdbf - viewer aka Deep View Free and powerful program Steep learning curve Interacts with modeling server available at Gale Rhodes’ Tutorial is at VTut/index.html VTut/index.html

Simplify the display  Show only alpha carbons  Color secondary structure  Turn 3 D display on

1HEW  Backbone as ribbon  Sidechains only in binding pocket  Substrate in yellow  Non-polar residues of binding pocket in turquoise

"Nothing in biology makes sense except in the light of evolution" Theodosius Dobzhansky

Homology bird wing bat wing human arm by Bob Friedman

homology vs analogy Homology (shared ancestry) versus Analogy (convergent evolution) A priori sequences could be similar due to convergent evolution bird wing butterfly wing bat wingfly wing

Related proteins Present day proteins evolved through substitution and selection from ancestral proteins. Related proteins have similar sequence AND similar structure AND similar function. In the above mantra "similar function" can refer to: identical function, similar function, e.g.: identical reactions catalyzed in different organisms; or same catalytic mechanism but different substrate (malic and lactic acid dehydrogenases); similar subunits and domains that are brought together through a (hypothetical) process called domain shuffling, e.g. nucleotide binding domains in hexokinse, myosin, HSP70, and ATPsynthases.

homology Two sequences are homologous, if there existed an ancestral molecule in the past that is ancestral to both of the sequences Homology is a "yes" or "no" character (don't know is also possible). Either sequences (or characters share ancestry or they don't (like pregnancy). Molecular biologist often use homology as synonymous with similarity of percent identity. One often reads: sequence A and B are 70% homologous. To an evolutionary biologist this sounds as wrong as 70% pregnant. Types of Homology Orthology: bifurcation in molecular tree reflects speciation Paralogy: bifurcation in molecular tree reflects gene duplication

Sequence Similarity vs Homology The following is based on observation and not on an a priori truth: If two (complex) sequences show significant similarity in their primary sequence, they have shared ancestry, and probably similar function. (although some proteins acquired radically new functional assignments, lysozyme -> lense crystalline).

The Size of Protein Sequence Space (back of the envelope calculation) For comparison the universe contains only about protons and has an age of about 5*10 17 seconds or 5*10 29 picoseconds. If every proton in the universe were a super computer that explored one possible protein sequence per picosecond, we only would have explored 5* sequences, i.e. a negligible fraction of the possible sequences with length 600 (one in about ). Consider a protein of 600 amino acids. Assume that for every position there could be any of the twenty possible amino acid. Then the total number of possibilities is 20 choices for the first position times 20 for the second position times 20 to the third.... = 20 to the 600 = 4* different proteins possible with lengths of 600 amino acids.

no similarity vs no homology If two (complex) sequences show significant similarity in their primary sequence, they have shared ancestry, and probably similar function. THE REVERSE IS NOT TRUE: PROTEINS WITH THE SAME OR SIMILAR FUNCTION DO NOT ALWAYS SHOW SIGNIFICANT SEQUENCE SIMILARITY for one of two reasons: a) they evolved independently (e.g. different types of nucleotide binding sites); or b) they underwent so many substitution events that there is no readily detectable similarity remaining. Corollary: PROTEINS WITH SHARED ANCESTRY DO NOT ALWAYS SHOW SIGNIFICANT SIMILARITY.

The central dogma Why might this be wrong or incomplete

Replication lagging and leading strand - strand bias

Transcription

 Prokaryotes  Eukaryotes

RNA processing  Intron types  RNA can be the catalyst Simple illustration of a pre-mRNA, with introns (top). After the introns have been removed via splicing, the mature mRNA sequence is ready for translation (bottom).

RNA enzymes:

Ribosome

Self-splicing introns

Group II intron

The RNA world concept  What arguments support an “RNA world” preceding a two biopolymer world?

Cenancestor (aka MRCA or LUCA) as placed by ancient duplicated genes (ATPases, Signal recognition particles, EF) The “Root” strictly bifurcating no reticulation only extant lineages based on a single molecular phylogeny branch length is not proportional to time The Tree of Life according to SSU ribosomal RNA (+) PHYLOGENY: from Greek phylon, race or class, and -geneia, born. “the origin and evolution of a set of organisms, usually of a species” (Wikipedia);

Tree, Web, or Coral of Life? Charles Darwin Photo by J. Cameron, 1869 Page B26 from Charles Darwin’s ( ) notebook (1837) “The tree of life should perhaps be called the coral of life, base of branches dead”

Which Type of Coral?

Darwin’s coral was a red algae (Bossea orbignyana) From Florian Maderspacher: “The captivating coral--the origins of early evolutionary imagery.” Curr Biol 16: R The captivating coral. According to the ideas of Horst Bredekamp, parts of the diagram in Darwin's origin of species (centre) more or less directly reflect the branching properties of a specimen Darwin collected himself.

The Coral of Life (Darwin)

Gene Transfer and Phylogenetic Reconstruction: Friends or Foes? Popular view  Gene transfer is a disruptive force in phylogenetic reconstruction. New view  Events of ancient gene transfer are valuable tools for reconstructing organismal phylogeny.

1. Any ancient gene transfer to the ancestor of a major lineage implicitly marks the recipient and descendents as a natural group. 2. The donor must exist at the same time or earlier than the recipient. Ancient HGTs

Gene “ping-pong” between different lineages can be used to build correlations between different parts of the tree/net of life. Presence of a transferred gene is a shared derived character that can be useful in systematics.