Biomedical subjects
Publications and source records attributed to Jeff Z Y Chen.
Using a newly developed Monte Carlo global optimization method called basin paving, we have performed an ab initio computation for the structure of Trp-cage based on the ECEPP/3 force field in vacuo. The lowest energy minimum has been located. Its corresponding configuration is comparable to the native structure of Trp-cage (PDB code 1L2Y) with a backbone root mean square deviation of 2.24 A.
We report a computational study of the small peptide Met-enkephalin based on the ECEPP/2 and ECEPP/3 force fields using the basin paving method. We have located a new global minimum when using the ECEPP/3 force field with peptide angles omega fixed at 180 degrees. With this new result, we can conclude that the lowest energy configurations of Met-enkephalin predicted based on all four versions of ECEPP have a classic gamma-turn centered at residue Gly3 and a beta-turn at residues Gly3-Phe4. However, minor differences between the structures also exist.
We study the dependence of folding time, nucleation site, and stability of a model beta-hairpin on the location of a cross-strand hydrophobic pair, using a coarse-grained off-lattice model with the aid of Monte Carlo simulations. Our simulations have produced 6500 independent folding trajectories dynamically, forming the basis for extensive statistical analysis. Four folding pathways, zipping-out, middle-out, zipping-in, and reptation, have been closely monitored and discussed in all seven sequences studied. A hydrophobic pair placed near the beta-turn or in the middle section effectively speed up folding; a hydrophobic pair placed close to the terminal ends or next to the beta-turn encourages stability of the entire chain.
We propose a global optimization procedure, basin paving, which is based on the combination of the optimization strategies behind basin hopping and energy landscape paving. As an example, we describe its application in the protein structure prediction by examining two well-studied peptides, where we have found lower potential energy minima than previously located. We also compare the statistics of the searching trajectories produced by basin paving, basin hopping, and energy landscape paving.
We report on Monte Carlo simulations of loop formation of an ideal flexible polymer consisting of N bonds with two reactive ends. We determine the first-passage time associated with chain looping that yields a conformation in which the end monomers are separated by a distance a--the reaction radius. In particular, our numerical results demonstrate how this time scale crosses over from tau(first) approximately N(3/2)/a to the a-independent tau(first) approximately N2 as N is increased. The existence and characteristics, of the two scaling regimes and the crossover between the two, are further illuminated by a scaling argument.
The multicanonical basin hopping (MUBH) method, which uses a multicanonical weight in the basin hopping (BH) Monte Carlo method, was found to be very efficient for global optimization of large-scale systems such as Lennard-Jones clusters containing more than 150 atoms. We have implemented an asynchronous parallel version of the MUBH method using the message passing interface (MPI) to take advantage of the full usage of multiprocessors in either a homogeneous or heterogeneous computational environment. Based on the intrinsic properties of the Monte Carlo method, this MPI implementation used the task parallelism to minimize interthread data communication. For a Co nanocluster consisting of N atoms, we have applied the asynchronous multicanonical basin hopping (AMUBH) method (for 181 < N < or = 200), together with BH (for 2 < or = N < 150) and MUBH (for 150 < or = N < or = 180), to search for the molecular configuration of the global energy minimum. AMUBH becomes the only practical computational scheme for locating the energy minimum within realistic computational time for a relatively large cluster.
A self-consistent-field theory for fluids of homogeneous wormlike polymers exhibiting a one-dimensional spatial variation is presented. We have extended the treatment of excluded-volume effects by adding an effective interaction term which describes the excluded volume between wormlike cylindrical segments and terminal (or end) segments of the polymer molecules. This enables us to find a smectic-A phase in the case of homogeneous semiflexible polymers. Using this framework, we have investigated the occurrence of smectic-A, nematic, and isotropic phases in the second-virial (Onsager) approximation. Phase diagrams are calculated for systems characterized by different rigidities (i.e., persistence lengths). For the case of infinitely rigid molecules, the nematic-smectic transition appears to be mostly second order. Systems of semiflexible molecules exhibit mainly a first-order smectic-nematic transition, and their isotropic-nematic-smectic triple points are accessed for different rigidity values. The nematic-smectic transition line is in good agreement with previous analytical calculations, which were also performed assuming the second-virial approximation. However, the values of the volume fraction at the nematic-smectic transition are large compared with computer simulation results, indicating limitations of the second-virial approximation.
We develop a theoretical approach to hairpin-loop formation of single-stranded (ss) DNA by treating the strand as a two-state system in which bases are either "stacked" or "unstacked." The looping kinetics of ssDNA is shown to be intrinsically different from that of a wormlike chain; it is mainly controlled by stacking-breakage probability, not by the mean curvature of loops, and highly sensitive to the composition of the loop as seen in recent experiments. Our estimate of a stacking energy for poly ( dA ), -3.9 kcal/mol, is consistent with known results.
We introduce a new optimization algorithm that combines the basin-hopping method, which can be used to efficiently map out an energy landscape associated with minima, with the multicanonical Monte Carlo method, which encourages the system to move out of energy traps during the computation. As an example of implementing the algorithm for the global minimization of a multivariable system, we consider the Lennard-Jones systems containing 150-185 particles, and find that the new algorithm is more efficient than the original basin-hopping method.
We present a molecular dynamics study of the conformational deformation of a minimalist beta-barrel protein model in two different types of hydrodynamic flows: uniform and elongational. We investigate the characteristics of protein stretching, paying special attention to the unfolding intermediate states and their relationship to the protein folding/unfolding problem. In the uniform flow simulations, one end of the modeled protein was tethered to a fixed point in space and the forced unfolding process was observed. The unfolding takes place via a few stages involving one or two intermediate states, depending on which end is tethered. The calculated force-extension curves show plateau regimes and hysteresis as the protein is stretched and refolded, in qualitative agreement with the experimental measurements. The physical behavior observed in our numerical simulations of the forced unfolding in an elongational flow is very different from that in uniform flow. The protein unfolds abruptly from the globular state to a fully stretched state without going through any observable intermediate states. From these observation, we stress that protein unfolding pathways under the influence of an external force are highly dependent on the mechanism of the exerted force.
The Monte Carlo technique is used to simulate the energy landscape and the folding kinetics of a minimal prion-like protein model. We show that the competition between hydrogen-bonding and hydrophobic interactions yields two energetically favored secondary structures, an alpha-helix and a beta-hairpin. Folding simulations indicate that the probability of reaching the alpha-helix form from a denatured random conformation is much higher than the probability of reaching the beta-sheet form, even though the beta-sheet has a lower energy. The existence of a lower energy beta-sheet state gives the possibility for the normal alpha-helix structure to take a structural transformation into the beta-sheet structure under external influences.
A protein molecule under the stress of an external denaturing force acting on a terminal end or on the entire molecule is expected to unfold, possibly through a few intermediate stages depending on the magnitude of the denaturing force. We have investigated two protein minimal models under various types of denaturing force fields using the collision molecular-dynamics simulation, in order to critically examine the relationship between the folding pathways observed in different protein denaturing experiments.
We examine the conformational properties of a random copolymer, containing a disordered hydrophobic/hydrophilic sequence of monomers, in the presence of a hydrophobic potential well. The model can be used to understand the structural properties of the adsorption of a protein molecule at a lipid-bilayer membrane, and the properties of a random copolymer at the surfaces of a microphase-separated layered polymer structure. Using a trial-potential treatment we demonstrate that a mainly hydrophilic chain may localize on the surface of the bilayer and that a mainly hydrophobic chain may have two typical conformations: localization on the surface or complete adsorption inside the two surfaces.
A double-stranded DNA molecule pulled with a force acting on the strand terminals exhibits a partially denatured structure or can be completely unzipped when the pulling force goes beyond a critical force. It has been suggested that accompanying the unzipping transition, various power-law properties exist. Through the numerical solution to a model that contains heterogeneous bonding interactions between bases on the two strands, we evaluated the critical forces and the extension-force curves for various degree of sequence disorderliness, and compared the numerical results with predictions from analytical approaches.
Searching through and conducting Monte Carlo folding simulations on 10(6) different 27 mer sequences, we have selected a prionlike lattice model whose energy spectrum and folding properties demonstrate characteristic prion behavior. The energetic competition and structural partition between two closely spaced energy minima yield unique kinetic and thermodynamic properties that can be qualitatively compared with experimental results. Folding simulations indicate that the probability of reaching the first excited state from a denatured random conformation is much higher than the probability of reaching the global energy-minimum state.