Biomedical subjects

Karl F Freed

Publications and source records attributed to Karl F Freed.

29 records · Page 2Linked to original sources

PubMed2005

A simple method for faster nonbonded force evaluations.

Accurate approximations are introduced for the evaluation of inverse interparticle distances such that square root or division operations are not required in the computation of interparticle interactions and forces. These generally applicable approximations are illustrated by incorporation into the protein simulation package TINKER along with several other speed enhancement strategies. With these modifications, implicit solvent Langevin dynamics simulations of proteins are performed factors of 4.6 times faster than the modified open source distributed program. Programming speedups are obtained by extensive vectorization, simplification of the inner loop to avoid IF statements, and by using lookup tables for the distance dependent "dielectric constant" in implicit solvent models. Benchmarks are provided for the all-atom, implicit solvent dynamics of Met-enkephalin, the villin headpiece, the B1 domain of protein-G, and barnase. We also discuss the more general applicability of the approximation methods to explicit solvent simulations and of look-up tables for other implicit solvent models such as the generalized Born models.

Algorithms↗

PubMed2004

Analytic density-functional self-consistent-field theory of diblock copolymers near patterned surfaces.

Analytical solutions are derived for the density profiles and the free energies of compressible diblock copolymer melts (or incompressible copolymer solutions) near patterned surfaces. The density-functional self-consistent-field theory is employed along with a Gaussian chain model for bonding constraints and a random mixing approximation for nonbonded interactions. An analytical solution is rendered possible by expanding the chain distribution function around an inhomogeneous reference state with a nontrivial analytical solution, by retaining the linear terms, and by requiring consistency with the homopolymer limit. The density profiles are determined by both real and complex roots of a sixth-degree polynomial that may easily be obtained by solving a generalized eigenvalue problem. This analytical formulation enables one to efficiently explore the large nine-dimensional parameter space and can serve as a first approximation to computationally intensive studies with more detailed models. Illustrative computations are provided for uniform and patterned surfaces above the order-disorder transition. The results are consistent with the previous self-consistent-field calculations in that lamellar ordering appears near the surface above the order-disorder transition and the lamella order perpendicular or parallel to the surface depending on the commensurability between the periods of the surface pattern and the density oscillations.

Journal Article↗

PubMed2004

Mixtures of lattice polymers with structured monomers.

The influence of monomer structure on the thermodynamic properties of lattice model polymer blends is investigated through Monte Carlo computations. The model of lattice polymers with monomer structure has been used extensively in the context of the lattice cluster theory (LCT), a thermodynamic theory for polymer mixtures in the liquid state. The Monte Carlo computations provide the first unequivocal test of the accuracy of the LCT predictions for binary mixtures of polymers with structured monomers. Four types of monomer structures are analyzed, corresponding to to the monomers of polyethylene, polypropylene, polyethylethylene, and polyisobutylene (PIB). Most computations use chains with M=12 and 24 beads and the total volume fraction of the beads is phi=0.6. Both structurally symmetric and asymmetric blends are investigated. For the symmetric case, the predictions of the LCT for the energies of mixing and the liquid-liquid coexistence curves are in qualitative agreement with the Monte Carlo computations, except for the PIB/PIB symmetric blend. For structurally asymmetric blends, the LCT does not capture contributions to the energy of mixing arising solely from structural differences between the components. Computational estimates of the nonideal entropy of mixing indicate that the LCT also underestimates the entropic cost of mixing chains with different structures, thus explaining some discrepancies between the theoretical and the Monte Carlo liquid--liquid coexistence curves.

Journal Article↗

PubMed2004

Flory-Huggins model of equilibrium polymerization and phase separation in the Stockmayer fluid.

The competition between chain formation and phase separation in the Stockmayer fluid (SF) of dipolar particles is analyzed using a renormalized Flory-Huggins model of equilibrium polymerization. Calculated critical properties (T(c), phi(c), Z(c)) for the SF compare favorably with simulations over a wide range of the dimensionless dipolar (or "sticking") energy mu*. We find that the polymerization transition preempts phase separation for a large mu*, i.e., (mu*)2 >22.

Journal Article↗

PubMed2003

Investigations into sequence and conformational dependence of backbone entropy, inter-basin dynamics and the Flory isolated-pair hypothesis for peptides.

The populations and transitions between Ramachandran basins are studied for combinations of the standard 20 amino acids in monomers, dimers and trimers using an implicit solvent Langevin dynamics algorithm and employing seven commonly used force-fields. Both the basin populations and inter-conversion rates are influenced by the nearest neighbor's conformation and identity, contrary to the Flory isolated-pair hypothesis. This conclusion is robust to the choice of force-field, even though the use of different force-fields produces large variations in the populations and inter-conversion rates between the dominant helical, extended beta, and polyproline II basins. The computed variation of conformational and dynamical properties with different force-fields exceeds the difference between explicit and implicit solvent calculations using the same force-field. For all force-fields, the inter-basin transitions exhibit a directional dependence, with most transitions going through extended beta conformation, even when it is the least populated basin. The implications of these results are discussed in the context of estimates for the backbone entropy of single residues, and for the ability of all-atom simulations to reproduce experimental protein folding data.

Algorithms↗

PubMed2003

Folding and misfolding of the papillomavirus E6 interacting peptide E6ap.

All-atom Langevin dynamics simulations have been performed to study the folding pathways of the 18-residue binding domain fragment E6ap of the human papillomavirus E6 interacting peptide. Six independent folding trajectories, with a total duration of nearly 2 micros, all lead to the same native state in which the E6ap adopts a fluctuating alpha-helix structure in the central portion (Ser-4-Leu-13) but with very flexible N and C termini. Simulations starting from different core configurations exhibit the E6ap folding dynamics as either a two- or three-state folder with an intermediate misfolded state. The essential leucine hydrophobic core (Leu-9, Leu-12, and Leu-13) is well conserved in the native-state structure but absent in the intermediate structure, suggesting that the leucine core is not only essential for the binding activity of E6ap but also important for the stability of the native structure. The free energy landscape reveals a significant barrier between the basins separating the native and misfolded states. We also discuss the various underlying forces that drive the peptide into its native state.

Biophysical Phenomena↗

PubMed2003

Large-scale context in protein folding: villin headpiece.

The villin headpiece folds autonomously in vitro forming three alpha-helical regions. Local propensities, however, strongly disfavor the formation of the C-terminal helix because most native residue pairs in that helix are hydrophobic/polar mismatches. Even the N-terminal helix is unfavored according to the AGADIR criterion. Our coarse-grained ab initio simulations reveal three-body correlations in which hydrophobic residues position to protect amide-carbonyl hydrogen bonds from attack by water, thus inducing the growth of the C-terminal helix and guiding the folding process. Similar correlations are also found in all-atom simulations with an implicit solvent model that accurately reproduces the results of simulations with explicit solvent molecules. The correlations establish a large-scale, many-body context that may be probed experimentally by introducing mutations of certain nonobvious residues that reside outside the native hydrophobic core but that are predicted to affect the folding rates and dynamics dramatically.

Alanine↗

PubMed2002

Analytical solution for steady-state populations in the self-assembly of microtubules from nucleating sites.

In addition to the biological importance of microtubules, which form a portion of the cellular cytoskeleton and a network for intracellular transport, the kinetics of microtubule self-assembly have generated great interest because individual microtubules exist in growing and decaying phases, with randomly occurring interconversions between them. Although a great deal is known concerning the microscopic details of these growth and decay processes, no description is available for the steady-state microtubule concentrations that are observed experimentally when microtubules are grown from nucleating sites. We generalize Hill's two-state model to include the dependence of the rates on tubulin concentration for systems where microtubules are grown from nucleating sites. An analytic solution is provided here to the resulting nonlinear, doubly infinite set of kinetic equations for the steady-state concentrations of both the growing and decaying phase microtubules as a function of the degree n of self-assembly and of the tubulin concentration. We also discuss the conditions for the stability of the steady state.

Biophysical Phenomena↗

PubMed2002

All-atom fast protein folding simulations: the villin headpiece.

We provide a fast folding simulation using an all-atom solute, implicit solvent method that eliminates the need for treating solvent degrees of freedom. The folding simulations for the 36-residue villin headpiece exhibit close correspondence with the landmark all-atom explicit solvent molecular dynamics simulations by Duan and Kollman (Duan & Kollman, Science 1998;282:740-744; Duan, Wang, & Kollman, Proc Natl Acad Sci USA 1998;95:9897-9902). Our implicit solvent approach uses only an entry-level single CPU PC with comparable throughput ( approximately 4 nsec/day) to the DK supercomputer simulation. The native state is shown to be stable. Our 200-nsec folding trajectory agrees with the DK simulation in displaying a burst phase, a rapid initial shrinkage, a highly native-like binding site structure, and more.

Animals↗

PubMed2002

Beyond Flory-Huggins theory: new classes of blend miscibility associated with monomer structural asymmetry.

Flory-Huggins (FH) theory is restricted to polymer mixtures whose monomers are structurally identical, a situation limited to isotopic blends and computer simulations. We investigate the influence of monomer structure on blend miscibility and scattering properties using the lattice cluster theory generalization of the FH model. Monomer structural asymmetry is shown to profoundly affect blend miscibility (T(c),phi(c)), chain swelling (T(theta)), and the scale (xi) and intensity [S(0)] of composition fluctuations. Four distinct blend miscibility classes are identified and experimental evidence for these classes is discussed.

Kinetics↗

PubMed2002

Long time dynamics of Met-enkephalin: comparison of explicit and implicit solvent models.

Met-enkephalin is one of the smallest opiate peptides. Yet, its dynamical structure and receptor docking mechanism are still not well understood. The conformational dynamics of this neuron peptide in liquid water are studied here by using all-atom molecular dynamics (MD) and implicit water Langevin dynamics (LD) simulations with AMBER potential functions and the three-site transferable intermolecular potential (TIP3P) model for water. To achieve the same simulation length in physical time, the full MD simulations require 200 times as much CPU time as the implicit water LD simulations. The solvent hydrophobicity and dielectric behavior are treated in the implicit solvent LD simulations by using a macroscopic solvation potential, a single dielectric constant, and atomic friction coefficients computed using the accessible surface area method with the TIP3P model water viscosity as determined here from MD simulations for pure TIP3P water. Both the local and the global dynamics obtained from the implicit solvent LD simulations agree very well with those from the explicit solvent MD simulations. The simulations provide insights into the conformational restrictions that are associated with the bioactivity of the opiate peptide dermorphin for the delta-receptor.

Biophysical Phenomena↗