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Protein Folding De novo Protein Design
Ranjit Ranbhor Soumendra Rana Anil Kumar Deepa Pednekar Kirti Patel Abhijit Tendulkar Sourav Das
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In the history of matter there are two clear episodes of organogenesis, natural and artificial. Dealing with stereogenic carbon the approaches are contrasted in the use of enantiomers. Convergent in approach, synthetic chemistry has seen huge investment of effort, intellect, even Nobel prizes, in asymmetric synthesis toward possibility of stereocontrol in organogenesis. Nature too harnessed stereochemistry but made selective use of only one enantiomer. Mysterious in the mechanism chiral resolution either preceded or accompanied biogenesis. The reasons are unclear but could be in the primacy of means rather than ends in biogenesis against ends rather than means in intelligent design; adopting an approach that was autonomous, divergent and evolutionary, Nature could dispense with retort and muffle-furnace and sacrificing an enantiomer it could gain in emergence of intellect, knowledge, even chemists, in bootstrapping principle of organogenesis. We are engaged in two complementary pursuits, examining biomolecular homochirality for ontological cum operational logic and exploring a middle path for intelligent design, combining advantages of polymer folding and stereocontrol of enantiomer structures. Tools used in our lab include software's like GROMACS, RIBOSOME, PROSS, DYANA, CYANA, visualization tools like Swiss Pdb Viewer, Mol Mol, peptide synthesis and characterization using methods like 2D NMR, CD. Projects completed, in progress and currently under incubation are summarized
Protein Folding Problem
Specific “folds” of an “unfolded” peptide.
Challenging contradictory views that short poly-alanines could be random-coils or PP-II, here we have demonstrated that octa-alanine actually populates a “native” fold in form of Type I’ b-hairpin, the most populous hair-pin of protein structure.
Existence of Specific “Folds” in Polyproline-II Ensembles of an “Unfolded” alanine Peptide Detected by Molecular Dynamics. Ramakrishnan, V.; Ranbhor, R.; Durani, S., J. Am. Chem. Soc, 126, 16332-16333 (2004).
The link between protein sequence and conformation could be stereochemically established.
We have found that poly-L stereochemistry could be critical in the link between sequence and conformation in polypeptide structure. Creating a conflict between hydrogen bonding and electrostatic interaction poly-L stereochemistry establishes a “yin-yang” in interamide interaction that seems fundamentally responsible for extreme conformational sensitivity of polypeptide structure to both solvent and sequence in amino acid side-chains.
The Link between Sequence and Conformation in Protein Structures could be Stereochemically Created. Ramakrishnan, V. Ranbhor, R, Kumar, A. and Durani, S. Submitted
Testing speed-limit in protein folding.
We have approached de novo protein design so as to stereochemically minimize the kinetic barriers in protein folding. According to "funnel" model, a "barrier-less" protein could serve as a “molecular rheostat”, being continuous in degree of structure or order in response to stimuli like temperature or pH.
A Rationally Designed Turn-Helix peptide. Dhanasekaran, M., Fabiola, F., Pattabhi V. and Durani S. J. Am. Chem. Soc. 121, 5575–5576 (1999)
Mechanism-based protein design: Attempted "nucleation-condensation" approach to a possible minimal helix-bundle protein.Mohanraja, K.; Dhanasekaran, M.; Kundu, B.; Durani, S. Biopolymers, 70(3), 355-363 (2004).
Computational Design of Proteins Stereochemically Optimized in Size, Stability and Folding Speed.Joshi, S., Rana, S., Wangikar, P. and Durani S., Submitted
Mapping elementary reaction paths in protein folding
Probing protein folding mechanisms, we are embarked on exhaustive enumeration of the folding pathways in suitable minimal protein models.
De novo Protein Design
Tailoring
proteins to specific stereochemical fits in conformation.
Being asymmetric in a-carbons,
protein structure could in principle exist in 2n stereoisomeric
forms. Only the poly-L isomer occurs naturally and is the building
block molecule of living state. We are embarked on a computational
approach to de novo design of proteins that are diversified in the
stereochemical structure at a-carbon. The designs
are approached over two step, racemization of
Simulated
Folding of Polypeptides Diversified in Molecular Tacticity. Implication for
Protein Folding and De novo Design.Ramakrishnan, V.;
Ranbhor, R.; Durani, S., Biopolymers, 78, 96-105 (2005).
Reengineering canonical b-hairpin to desired morphological forms.
Demonstrating molecular design by stereochemical fit in conformation, the canonical b-hairpin fold has been reengineered as “bracelet”, “boat” and “canoe” shaped molecular folds.
a-Polyamides as Potential Stereochemical Customizable Proteins. A Mini-b Protein Reprogrammed as a Cationophore. Rana, S.; Kundu, B.; Durani, S. Submitted.
A Small Peptide Stereochemically Customized as a Globular Fold with a Molecular Cleft.Rana, S.; Kundu, B.; Durani, S. Chem. Comm., 2, 207-209 (2005).
Stereospecific Peptide Folds. A Rationally Designed Molecular Bracelet. Rana, S.; Kundu, B.; Durani, S.Rana, S.; Kundu, B.; Durani, S. Chem. Comm., 21, 2462-2463 (2004).
Configurationally Guided Peptide Conformational Motifs. Crystal Structure of a LDLDDL type Hexapeptide Fold.F. Fabiola, V. Pattabhi, S. Rawale, E. B. Raju and S. Durani Chem. Comm., 1379-80 (1997)
Molecular design by simulated evolution in catalysis and self-assembly.
Combining evolutionary method with rational design, we are embarked on design of polypeptides that are stereochemically optimized to function as catalytic systems or self organize as supramolecular systems.
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