CRANKITE: a fast polypeptide backbone conformation sampler

Background: CRANKITE is a suite of programs for simulating backbone conformations of polypeptides and proteins. The core of the suite is an efficient Metropolis Monte Carlo sampler of backbone conformations in continuous three-dimensional space in atomic details. Methods: In contrast to other programs relying on local Metropolis moves in the space of dihedral angles, our sampler utilizes local crankshaft rotations of rigid peptide bonds in Cartesian space. Results: The sampler allows fast simulation and analysis of secondary structure formation and conformational changes for proteins of average length

Theory of Side-Chain Liquid Crystal Polymers: Bulk Behavior and Chain Conformation

We study the thermodynamics and chain conformation of side-chain liquid crystal polymers (SCLCPs) in the bulk using the self-consistent-field approach and a new model to account for the coupling between the orientation of the side-chain liquid-crystal (LC) groups and that of the backbone segments. The new model accounts for both a global coupling between the polymer backbone and the nematic field and a local coupling between the polymer backbone and its attached LC group. Here, the terms global and local refer to the chemical (backbone) distance between the groups. A phenomenological parameter is introduced to represent the coupling strength and nature of the attachment, i.e., end-on vs side-on. The nematic field is shown to control the chain conformation through both the global and the local coupling effects. For the side-on SCLCPs, these two coupling effects act cooperatively so that the chain conformation is always prolate. For the end-on SCLCPs, these two effects act competitively. The chain conformation can be either oblate or prolate in this case, and depends on the relative strengths of these two couplings. On the other hand, the chain conformation also affects the nematic field, primarily through the global coupling. The prolate conformation enhances the nematic field and increases the phase transition temperature, whereas the oblate conformation frustrates the nematic field and decreases the transition temperature. The nematic order parameter is found to be determined mainly by the reduced temperature, and is not sensitive to the coupling effects. Furthermore, we show that the grafting density of the LC side groups has a significant effect on the chain conformation due to the orientational competition between the LC attached and unattached segments. For the end-on SCLCPs with lower graft density, the conformation of the chain backbone can be oblate at higher temperatures and prolate at lower temperatures, in agreement with the re-entrant nematic phase observed in experiments

Temperature dependent photoluminescence of organic semiconductors with varying backbone conformation

We present photoluminescence studies as a function of temperature from a series of conjugated polymers and a conjugated molecule with distinctly different backbone conformations. The organic materials investigated here are: planar methylated ladder type poly para-phenylene, semi-planar polyfluorene, and non-planar para hexaphenyl. In the longer-chain polymers the photoluminescence transition energies blue shift with increasing temperatures. The conjugated molecules, on the other hand, red shift their transition energies with increasing temperatures. Empirical models that explain the temperature dependence of the band gap energies in inorganic semiconductors can be extended to explain the temperature dependence of the transition energies in conjugated molecules.Comment: 8 pages, 9 figure

Effective Sampling in the Configurational Space by the Multicanonical-Multioverlap Algorithm

We propose a new generalized-ensemble algorithm, which we refer to as the multicanonical-multioverlap algorithm. By utilizing a non-Boltzmann weight factor, this method realizes a random walk in the multi-dimensional, energy-overlap space and explores widely in the configurational space including specific configurations, where the overlap of a configuration with respect to a reference state is a measure for structural similarity. We apply the multicanonical-multioverlap molecular dynamics method to a penta peptide, Met-enkephalin, in vacuum as a test system. We also apply the multicanonical and multioverlap molecular dynamics methods to this system for the purpose of comparisons. We see that the multicanonical-multioverlap molecular dynamics method realizes effective sampling in the configurational space including specific configurations more than the other two methods. From the results of the multicanonical-multioverlap molecular dynamics simulation, furthermore, we obtain a new local-minimum state of the Met-enkephalin system.Comment: 15 pages, (Revtex4), 9 figure

Exploring the Levinthal limit in protein folding

According to the thermodynamic hypothesis, the native state of proteins is uniquely defined by their amino acid sequence. On the other hand, according to Levinthal, the native state is just a local minimum of the free energy and a given amino acid sequence, in the same thermodynamic conditions, can assume many, very different structures that are as thermodynamically stable as the native state. This is the Levinthal limit explored in this work. Using computer simulations, we compare the interactions that stabilize the native state of four different proteins with those that stabilize three non-native states of each protein and find that the nature of the interactions is very similar for all such 16 conformers. Furthermore, an enhancement of the degree of fluctuation of the non-native conformers can be explained by an insufficient relaxation to their local free energy minimum. These results favor Levinthal's hypothesis that protein folding is a kinetic non-equilibrium process.FCT - Foundation for Science and Technology, Portugal [UID/Multi/04326/2013]; Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP); Conselho Nacional de Desenvolvimento Cientia co e Tecnologico (CNPq

Molecular modeling of an antigenic complex between a viral peptide and a class I major histocompatibility glycoprotein

Computer simulation of the conformations of short antigenic peptides (&lo residues) either free or bound to their receptor, the major histocompatibility complex (MHC)- encoded glycoprotein H-2 Ld, was employed to explain experimentally determined differences in the antigenic activities within a set of related peptides. Starting for each sequence from the most probable conformations disclosed by a pattern-recognition technique, several energyminimized structures were subjected to molecular dynamics simulations (MD) either in vacuo or solvated by water molecules. Notably, antigenic potencies were found to correlate to the peptides propensity to form and maintain an overall a-helical conformation through regular i,i + 4 hydrogen bonds. Accordingly, less active or inactive peptides showed a strong tendency to form i,i+3 hydrogen bonds at their Nterminal end. Experimental data documented that the C-terminal residue is critical for interaction of the peptide with H-2 Ld. This finding could be satisfactorily explained by a 3-D Q.S.A.R. analysis postulating interactions between ligand and receptor by hydrophobic forces. A 3-D model is proposed for the complex between a high-affinity nonapeptide and the H- 2 Ld receptor. First, the H-2 Ld molecule was built from X-ray coordinates of two homologous proteins: HLA-A2 and HLA-Aw68, energyminimized and studied by MD simulations. With HLA-A2 as template, the only realistic simulation was achieved for a solvated model with minor deviations of the MD mean structure from the X-ray conformation. Water simulation of the H-2 Ld protein in complex with the antigenic nonapeptide was then achieved with the template- derived optimal parameters. The bound peptide retains mainly its a-helical conformation and binds to hydrophobic residues of H-2 Ld that correspond to highly polymorphic positions of MHC proteins. The orientation of the nonapeptide in the binding cleft is in accordance with the experimentally determined distribution of its MHC receptor-binding residues (agretope residues). Thus, computer simulation was successfully employed to explain functional data and predicts a-helical conformation for the bound peptid

Role of Peptide Backbone Conformation on Biological Activity of Chemotactic Peptides

To investigate the role of peptide backbone conformation on the biological activity of chemotactic peptides, we synthesized a unique analog of N-formyl-Met-Leu-Phe-OH incorporating the C α,α disubstituted residue, dipropylglycine (Dpg) in place of Leu. The conformation of the stereochemically constrained Dpg analog was examined in the crystalline state by x-ray diffraction and in solution using NMR, IR, and CD methods. The secretagogue activity of the peptide on human neutrophils was determined and compared with that of a stereochemically constrained, folded type II β-turn analog incorporating 1-aminocyclohexanecarboxylic acid (Ac6c) at position 2 (f-Met- Ac6c -Phe-OMe), the parent peptide (f-Met-Leu-Phe-OH) and its methyl ester derivative (f-Met-Leu-Phe-OMe). In the solid state, the Dpg analog adopts an extended β-sheet-like structure with an intramolecular hydrogen bond between the NH and CO groups of the Dpg residue, thereby forming a fully extended (C5) conformation at position 2. The ϕ and ψ values for Met and Phe residues are significantly lower than the values expected for an ideal antiparallel beta conformation causing a twist in the extended backbone both at the N and C termini. Nuclear magnetic resonance studies suggest the presence of a significant population of the peptide molecules in an extended antiparallel β conformation and the involvement of Dpg NH in a C5 intramolecular hydrogen bond in solutions of deuterated chloroform and deuterated dimethyl sulfoxide. IR studies provide evidence for the presence of an intramolecular hydrogen bond in the molecule and the antiparallel extended conformation in chloroform solution. CD spectra in methanol, trifluoroethanol, and trimethyl phosphate indicate that the Dpg peptide shows slight conformational flexibility, whereas the folded Ac6c analog is quite rigid. The extended Dpg peptide consistently shows the highest activity in human peripheral blood neutrophils, being approximately 8 and 16 times more active than the parent peptide and the folded Ac6c analog, respectively. However, the finding that all four peptides have ED50 (the molar concentration of peptide to induce half-maximal enzyme release) values in the 10(-8)-10(-9) M range suggests that an induced fit mechanism may indeed be important in this ligand-receptor interaction. Moreover, it is also possible that alterations in the backbone conformation at the tripeptide level may not significantly alter the side chain topography and/or the accessibility of key functional groups important for interaction with the receptor