Possible Origin of Chirality in Proteins

1. Possible Origin of Chirality in Proteins Malcolm E. Schrader Institute of Chemistry The Hebrew University of Jerusalem ILASOL 27 DECEMBER 1, 2013 The Weizmann Institute of Science

2. Chromatographic column hypothesis • In today’s talk I review previous, and explore additional, consequences of my approach claiming that prebiotic small atmospheric molecules concentrated and reacted, in a quasi-chromatographic column, on land rather than in the oceans.

3. Mainline Approach to Chemical Evolution on Earth: Oparin 1. Atmosphere at time of origin of chemical evolution was reducing 2. Molecules from reducing atmosphere dissolved in oceans. 3.Under energetic activation they ultimately polymerized to biological polymers.

4. UREY Continued postulate of reducing atmosphere from his own model of planet Earth formation. a. Slowly cooling planet b. Presence of iron in crust removed oxygen from atmosphere c. “Atmosphere mainly”: H2, CH4, N2, NH3 d.    “Smaller amounts”: CO2, CO

5. ATMOSPHERIC COMPOSITION REVISITED 1.Earth cooled fast   2.   Iron core formed fast   3.   Thus removing an important oxygen getter from contact with atmosphere. 4. Newly favored atmospheric composition: N2, CO2, H20, and H2, CO in small amounts.

6. Possible results • Pinto et al showed that HCHO could be produced from this nearly neutral atmosphere. • Zahnle showed that if CH4 were also part of this atmosphere, HCN could be produced. However, he pointed out, CH4 could not be part of the model of this nearly neutral atmosphere • We pointed out that prebiotic CH4, however, was still being emitted in local spots.

9. RNA OLIGOMER UNIT Ferris, 2004

10. Cyanomethanol Hypothesis HCN mixes with similarly deposited formaldehyde from raindrops HCN + HCHO → CH2(CN)OH 5CH2(CN)OH → adenosine + H2O This provides explanation for pentose (rather than hexose) inclusion in RNA/DNA Schrader, M. E. (2009) J. Geophys. Res. 114, D15305

11. Polypeptide (Protein Backbone) from Cyanomethanol. 1 • H H H • NΞC─C─OH+NΞC─C─OH + NΞC─C─OH • H H H • ↓ ↓↓↓ • H H H • NΞC─C─C ─ N─C ─ C ─ N─ C ─ OH • H ║H H ║ H H • O O

12. Polypeptide (Protein Backbone) from Cyanomethanol. 2 • H H H • NΞC─C─OHNΞC─C─OHNΞC─C─OH • H H H • ↓ ↓↓↓ • H H H • NΞC─C─N ─ C─C ─ N ─ C─ C ─ OH • H H ║ H H ║ H • O O

13. Enthalpy (kcal/mole)1. • break make • C ─OH 90 CH2 ─ CO 72 • C ≡ N 212.6 CO ─ NH 72.8 • CH2 ─ OH 101.5 NH ─ CH2 72.8 • N≡C ─ CH2 95.3 C = O 176 • N ─ H 98.8 • amide resonance 20 • Total 499.4 512.4

14. Enthalpy (kcal per mole) 2. • Breaking energy Forming energy • H2C ─ OH 90 O ═ C 176 • N ≡ C─CH2 212.6 O═C ─ NH 72.8 • CH2O ─ H 101.5 N ─ H 98.8 • H2C ─ NH 72.8 • amide resonance 20 • Total 404.1 Total 429.4

15. Likely mechanism • It can be seen that stronger bonds must be broken in mechnism 1 over mech 2. While thermodynamically the difference between making and breaking bonds should be the same in each case, the larger values in mechanism 1 imply a greater activation energy. • We therefore assume mechanism 2 to be correct in all cases.

16. Chromatographic Approach and Chirality • The foregoing approach can lead to complete chirality in proteins. • To understand how, we first review the presently accepted chemical origin of proteins

17. Chirality in Proteins • Chirality. The conventional approach to chirality in proteins is based on the assumption that proteins were originally built up from the hydrolyzed segments that we now obtain, and assumes that they were formed by the condensation of these amino acid segments.

18. Conventional Approach • Nearly every one of these amino acids obtained from protein hydrolysis has an alpha carbon atom of the same chirality, called levo for this case of proteins. Thus, in the condensation written below, any amino acid, RCHNH2COOH, where R is any organic group found in amino acids, will react with another amino acid, where R may be the same or different for each segment, to form a protein, as follows:

19. Conventional Approach • R O O O • │ ║ H ║ H ║ • HN – Cα – C – OH + HN – Cα – C – OH + HN – Cα – C – OH • H H H │ H │ • R’ R’’ • ↓ [5] • R O O O • │ ║ H ║ H ║ • HN – Cα – C – N − Cα – C – N - Cα – C – OH + 2H2O • H H H │ H │ • R’ R’’

20. Conventional Approach • Thus, from this point of view, it is a mystery why the Cα groups in the backbone of the resulting proteins, are all of the same chirality. For example, if we take the first amino acid on the left as levo, then the other two can be dextro, as indicated, and the succeeding amino acids may also be one or the other. There is no reason why all the monomers (amino-acids) should be either d or l exclusively.

21. Peptide/polypeptide adsorption • If the peptide and polypeptide are formed from an adsorbed monomer, without including any R groups, the situation changes.

22. Adsorption to solid surface • It is a basic tenate of our approach that the prebiotic oligomers and polymers were formed by monomers flowing through or on mineral surfaces which act as a quasi-chromatographic column. Thus they may be regarded as having been essentially adsorbed to a solid surface.

23. Adsorption 2. • Adsorption of even small molecules are now known to often adsorb in the form of separate islands. • This phenomenon has now become popularly described as “self assembly”. • Of course, what is really governing the phenomenon is free energy of adsorption. • Molecules from the environment adsorb and desorb in amounts governed by the negative free energy of adsorption. Considering that alone, no islands are formed.

24. Adsorption 3. • However, adding to the free energy of adsorption of individual molecules, there is possibility of attractive lateral interaction between adsorbed molecules, thus islands may be formed. • This essentially two dimensional product suggests, intuitively, due to the spatial restriction, a possible cause of chirality.

25. Recent mineral studies • There has recently been a commendable rash of speculation on the possibility of chirality in mineral surfaces forcing chirality on adsorbed amino acids. • (This approach is usually combined with the classical “soup” assumption of origin of life speculation, so that the soup somehow comes in contact with the minerals. By contast, our approach involves a land based phenom, with water, possibly rain, as eluent.)

26. Two dimensions • At any rate our approach here differs from those attempts in that we focus solely on the dimensionality of the adsorbing polar surface, without assuming it to have any intrinsic chiral properties.

27. Cyanomethanol adsorption 1. • We now examine the approximate nature of the adsorption of cyanomethanol, our hypothesized monomer, to a two dimensional polar surface. • The monomer is a tetragon, a triangle of which rests on a surface with a group or atom in each of the 3 corners of the triangle and a fourth corner perpendicular to plane of surface. A carbon atom is in the middle above plane of surface..

28. Adsorbed cyanomethanol H c N≡C OH

29. Adsorbed cyanomethanol H c H N≡C OH

30. Cyanomethanol adsorption 2. • Since the surface is polar, both the CN and OH groups must be in the triangle adsorbed to the surface. Thus, the third corner is occupied by an H atom, and the other H atom is perpendicular to surface. • In terms of future reaction, then, one H is on surface relatively inaccessible, while the other protrudes and is very accessible.

31. Cyanomethanol adsorption 3. • Therefore, due to two dimensional confinement of the molecule on the surface. the two hydrogens are no longer equivalent • The adsorbed cyanomethanol monomer is then here called quasi-chiral.

32. 2-dimensional polymerization • In order for the CM molecules to polymerize in a straight line as pictured, a l molecule as pictured, could be next to another l molcule, as pictured, since the CN group requires an OH for reaction.

33. 2-dimensional polymerization of CM • H H C C C≡N N≡C OH OH

34. enantiomers N≡C OH OH C≡N

35. Possible reaction • The 2 enantiomers as pictured cannot react along a straight line

36. However, if a d group near the l is rotated, in the plane, there can indeed be reaction, which can be propagated in 2 dimensions regardless of l or d chirality. • So, two dimentional confinement is not sufficient to force pure l (or d) polymerization.

37. Enantiomers.2 OH H CN N≡C OH

38. One dimensional adsorption • Now, consider a partially opened book. • The interface between the two exposed pages now consists of a more or less one dimensional space in which small particles can comfortably nest. • Transform the picture to a nano sized crevice in a mineral surface.

39. Adsorption in crevice H H OH OH NC NC

40. One dimensional adsorption of cyanomethanol • The two polar groups will now adsorb to the bottom of a crevice where they each interact with two surfaces at once. • The H of the triangle containing the adsorbed polar groups is now assumed to lean back to one of the joined surfaces which form the crevice.

41. One-d adsorption • The other surface forming the crevice is short, and the H perpendicular to the triangle protrudes and is available for reaction. • Ultimately, R groups of various types replace the protruding H’s and the alpha carbons all remain completely levo (or dextro).

42. Glycine condensation • The same considerations may be applied to the conventional proposed condensation mechanism of prebiotic polypeptide/protein formation provided that the monomer is glycine and the condensation takes place in a one-dimensional crevice on a quasi-chromatographic land-based column which removes the H2O product.

43. Quasi-chirality from adsorbed glycine • O O O • H ║ H ║ H ║ • HN – Cα – C – OH + HN – Cα – C – OH + HN – Cα – C – OH • H H H H H H • ↓ [5] • O O O • H ║ H ║ H ║ • HN – Cα – C – N − Cα – C – N - Cα – C – OH + 2H2O • H H H H H H

44. Conclusions 1. • Replacement of the conventional water based “soup” approach to prebiotic polymerization, with the the land-based “chromatographic column” approach, results in possibilities for complete chirality of proteins. • Specifically, the monomer, preferably cyanomethanol, can adsorb and react in a largely one-dimensional crevice to form a completely l (or d) chiral protein.

45. Conclusions 2. • Many factors must fall into place, spatially and temporaly, for the process to succeed. • A low probability may therefore have to be assigned to the occurrence of chemical evolution on the planet Earth. • Does this support or detract from the theory?

46. Acknowledgment • The author thanks Shmuel Yariv and Yitzhak Lapides for their valuable comments.

47. Thank you for your interest!!