The role of form in molecular biology. Conceptual parallelism with developmental and evolutionary biology

Transcription

1 The role of form in molecular biology Conceptual parallelism with developmental and evolutionary biology Laura Nuño de la Rosa (UCM & IHPST) KLI Brown Bag talks 2008

2 The irreducibility of biological form Common conceptual context Anti-reductionist epigenetic vs. Reductionist molecular approaches A more fundamental question Does molecular biology imply a reductionist 'antimorphological' vision of the very biological macromolecules (BMF) (i.e. proteins, DNA, RNA)?.

3 BM as exemplar objects for theoretical bio Genotype = Sequence Phenotype = Structure nucleotides, amino acids Double helix, 3D structures of RNA & proteins Fitness = Function

4 Conceptual parallelisms

5 Outline The definition of BMF The constitution of BMF Wholes and modules Structures and sequences The generation of BMF Folding Evolutionary transformation Form and function

6 The definition of BMF

7 Structure and Shape

8 Structure and Shape

9 Structure and Shape All-atom backbone conformation solvent-accessible surface Representations of the 3D structure of triose phosphate isomerase:

10 Static and Dynamic structures Naturphilosophie vs. Linnaeus Systematics Waddington vs. Thom Ontogenetic trajectories vs. developmental stages Nayra García on Henri Bergson

11 Static and Dynamic BM structures Crystallography Geometric-based definition of protein conformation as a set of atomic coordinates RMN Structural flexibility, proteins as dynamical systems Thermodynamics definition of protein structure (Kaltashov & Eyles 2005)

12 The constitution of BMF

13 Wholes & 'morphological' parts phenotype is neither atomistic nor holistic, but modular (Griffiths 2002) Organizational/Synchronic view: Modules are units of phenotypic integration (Eble 2002) Structural homologues Diachronic view: Homologues as variational units/units of phenotypic evolution (Wagner)

14 BM wholes & modules Modules: secondary structure, structural motifs, structural domains Relative independence Modules families independent evolution bhlh structural motif of the AhR protein: 2 helices connected by a loop

15 Structural motif families (Kaltashov & Eyles 2005)

16 Wholes & 'material' parts The discreteness of morphospace The asymmetry of the genotype-phenotype mapping The clustering of organisms in phenotypic space (Alberch 1982)

17 BM wholes & 'material' parts The Linear Sequence Hypothesis (LSH) The combinatorial definition of genetic information (Watson 1958) Population genetics Linear arrangement vs. physical shape (Shrödinger 1944) The generalized structure of the DNA

18 Sequence-BM structure mapping Asymmetry "the fold universe appears to be dominated by a relatively small number of giant attractors, each accommodating a large number of unrelated sequences (c.f. Zhang & DeLisi 2001) as a general rule, structure is more robust than sequence (Wood & Pearson 1999) Structural variations there is no one generic structure for DNA and RNA, but variations on common themes of structure (Alberts 2003)

19 Theoretical approaches Idealism protein folds as real timeless structures (Denton et al. 2002) 'Molecular evo-devo' Morphological information => Folding

20 The generation of BMF

21 Development & Folding

22 Development & Folding Reductionism development as a molecular 'computing' of the embryo (Rosenberg 1997) All of the information necessary for folding the peptide chain into its 'native' structure is contained in the amino acid sequence of the peptide. (Garret & Grisham 1999) Afinsen's experiments

23 Development & Folding Reductionism development as a molecular 'computing' of the embryo (Rosenberg 1997) All of the information necessary for folding the peptide chain into its 'native' structure is contained in the amino acid sequence of the peptide. (Garret & Grisham 1999) Afinsen's experiments Objections The 'context objection' (Delehanty 2005) The emergence of new irreducible topological relations in the three-dimensional biological space

24 Protein structure prediction 'Levinthal paradox' (1968) Energy landscapes 1 folding may proceed through multiple pathways, rather than a single route; 2 regardless of the starting point, the conformational space is progressively funnelled. The generation of BMF depends on the structural landscape that is generated during the very process of folding.

25 Evolutionary transformation

26 BM evolution RNA model (Shuster, Fontana, Stadler...)

27 The sequence-structure map RNA folding Accessibility topology of shape space (Stadler et al. 2001; Schuster & Stadler)

28 The sequence-structure map RNA folding Accessibility topology of shape space (Stadler et al. 2001; Schuster & Stadler)

29 Evolutionary consequences RNA model (Shuster, Fontana, Stadler...)

30 Evolutionary consequences Structural homology evolvability constraints punctuated equilibria innovation

31 Form & Function

32 The common view External Function Sequence = Structure <= Natural Selection MB Function derives from three-dimensional structure and the three-dimensional structure is established by the amino acid sequence (Lodish et al. 2004)

33 Internalism Internal definition of function The 'semantic' properties of form 'Morphological ethology' (Thom), biomechanics Internal constraints to function Exaptation, Co-option Form & Function

34 Internal definition of function Forms coupling Lock-key model, induced theory Evolutionary consequences Fitness as an internal parameter Molecular mechanics

35 Topological constraints cccdna

36 Topological constraints understanding the topology of DNA and how the cell both accommodates and exploits topological constraints during DNA replication, transcription, and other chromosomal transactions is of fundamental importance in molecular biology. (Watson et al. 2004)

37 Exaptation, Co-option Homologous proteins with different functions Modularity

38 Conclusions The role of dynamics BMF are modular Form is not reducible to sequence. Forms are robust in the face of both mutational challenges and conformational disturbances Form cannot be dissociated from the understanding of the process governing its generation. Form is a fundamental category in the understanding of Function

39 A geometrical-topological treatment of molecular substances in contrast with the informational approach that has dominated mainstream philosophy of biology. The fact that many traditional problems regarding Form reappear at the molecular level doesn't mean that they are going to be solved at this level, but that reductionism will have to look, on the first place, at the many problems that Form poses in the very field of molecular biology.