Molecular dynamics simulations of endogenous opioid peptide dynorphin in explicit bilayers

Integral membrane proteins account for about 30% of the genes and they participate in diverse functions including signaling and transport across membranes. G-Protein Coupled Receptors (GPCRs), channel proteins and pumps form important families of integral membrane proteins. For example more than 50% of the targets for developing new drugs are GPCRs. Membrane proteins are difficult to crystallize and hence understanding the structure-function relationships of these important classes of proteins have become difficult. The number of membrane protein crystal structures is yet to reach 100 while more than 15,000 globular protein structures are known at atomic resolution.

In this scenario, computational studies to understand the structure-function relationships of these biologically important membrane proteins have become especially valuable. Our lab is interested in analyzing the membrane protein crystal structures and we use bioinformatics tools to study the sequences in relation to their structures. We particularly focus on the interactions within the transmembrane helical proteins. Molecular dynamics simulations in explicit lipid bilayers are carried out to understand the stability and energetics of TM interactions. Such studies help to design the mutagenesis experiments and to develop strategies in the modeling of membrane proteins.

Many peptide hormones interact with the receptors that are integral membrane proteins. These hormones are involved in important physiological functions and have clinical applications. For example, opioid peptides like dynorphin are implicated in analgesia and pituitary adenylate cyclase activating peptide (PACAP) is involved in the control of many autonomic and sensory functions. These peptides are small and flexible in solution and hence understanding the molecular mechanism of peptide-receptor interactions has become very difficult. It has been proposed that these peptide hormones first bind to the biological membranes before they interact with their receptor proteins and the conformation induced by the membrane is likely to be the bioactive conformation. Our lab is interested to characterize the structural properties of the small peptide hormones in explicit lipid bilayers. Molecular dynamics simulations of dynorphin have shown the importance of basic and aromatic residues in stabilizing and orienting the peptide conformations within the bilayers. Simulations also revealed the possible reason for des-tyr dynorphin's loss of opioid-binding activity.

Selected publications:

1. R. Sankararamakrishnan and H. Weinstein, Positioning and stabilization of dynorphin peptides in membrane bilayers: the mechanistic role of aromatic and basic residues revealed from comparative MD simulations,J. Phys. Chem. B 106, 209 - 218 (2002).
2. R. Sankararamakrishnan and H. Weinstein, Molecular dynamics simulations predict a tilted orientation for the helical region of dynorphin A(1-17) in dimyristoylphosphatidylcholine bilayers, Biophys. J. 79, 2331 - 2344 (2000) (Cover Illustration).
3. R. Sankararamakrishnan, K. Konvicka, E.L. Mehler and H. Weinstein, Solvation in simulated annealing and high-temperature molecular dynamics of proteins: A restrained water droplet model, Int. J. Quantum Chem. 77, 174-186 (2000).
4. C. Singh, R. Sankararamakrishnan, S. Subramaniam and E. Jakobsson, Solvation, water permeation, and ionic selectivity of a putative model for the pore region of the voltage-gated sodium channel, Biophys. J. 71, 2276-2288 (1996).
5. R. Sankararamakrishnan, C. Adcock and M.S.P. Sansom, The pore domain of the nicotinic acetylcholine receptor: Molecular modeling, pore dimensions and electrostatics, Biophys. J. 71, 1659-1671 (1996).
6. M.S.P. Sansom, R. Sankararamakrishnan and I.D. Kerr, Modelling membrane proteins using structural restraints, Nature Struct. Biol. 2, 624-631 (1995).
7. R. Sankararamakrishnan and S. Vishveshwara, Geometry of proline-containing alpha-helices, Int. J. Peptide Protein Res. 39, 356-363 (1992),
   

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