We report the modification and parametrization of the united-residue (UNRES) force field for energy-based protein structure prediction and protein folding simulations. We tested the approach on three training proteins separately: 1E0L (beta), 1GAB (alpha), and 1E0G (alpha + beta). Heretofore, the UNRES force field had been designed and parametrized to locate native-like structures of proteins as global minima of their effective potential energy surfaces, which largely neglected the conformational entropy because decoys composed of only lowest-energy conformations were used to optimize the force field. Recently, we developed a mesoscopic dynamics procedure for UNRES and applied it with success to simulate protein folding pathways. However, the force field turned out to be largely biased toward -helical structures in canonical simulations because the conformational entropy had been neglected in the parametrization. We applied the hierarchical optimization method, developed in our earlier work, to optimize the force field; in this method, the conformational space of a training protein is divided into levels, each corresponding to a certain degree of native-likeness. The levels are ordered according to increasing native-likeness; level 0 corresponds to structures with no native-like elements, and the highest level corresponds to the fully native-like structures. The aim of optimization is to achieve the order of the free energies of levels, decreasing as their native-likeness increases. The procedure is iterative, and decoys of the training protein(s) generated with the energy function parameters of the preceding iteration are used to optimize the force field in a current iteration. We applied the multiplexing replica-exchange molecular dynamics (MREMD) method, recently implemented in UNRES, to generate decoys; with this modification, conformational entropy is taken into account. Moreover, we optimized the free-energy gaps between levels at temperatures corresponding to a predominance of folded or unfolded structures, as well as to structures at the putative folding-transition temperature, changing the sign of the gaps at the transition temperature. This enabled us to obtain force fields characterized by a single peak in the heat capacity at the transition temperature. Furthermore, we introduced temperature dependence to the UNRES force field; this is consistent with the fact that it is a free-energy and not a potential energy function. beta 相似文献
Summary: A reduced high‐coordination lattice protein model and the Replica Exchange Monte Carlo sampling were employed in de novo folding simulations of a set of representative small proteins. Three distinct situations were analyzed. In the first series of simulations, the folding was controlled purely by the generic force field of the model. In the second, a bias was introduced towards the theoretically predicted secondary structure. Finally, we superimposed soft restraints towards the native‐like local conformation of the backbone. The short‐range restraints used in these simulations are based on approximate values of ϕ and ψ dihedral angles, which may simulate restraints derived from inaccurate experimental measurements. Incorporating such data into the reduced model required developing a procedure, which transforms the ϕ and ψ coordinates into coordinates of the protein alpha carbon trace. It has been shown that such limited data are sufficient for de novo determination of three‐dimensional structures of small and topologically not too complex proteins.
Protein folding based on secondary structure prediction and simulated torsion angles data. 相似文献
The implementation of molecular dynamics (MD) with our physics-based protein united-residue (UNRES) force field, described in the accompanying paper, was extended to Langevin dynamics. The equations of motion are integrated by using a simplified stochastic velocity Verlet algorithm. To compare the results to those with all-atom simulations with implicit solvent in which no explicit stochastic and friction forces are present, we alternatively introduced the Berendsen thermostat. Test simulations on the Ala(10) polypeptide demonstrated that the average kinetic energy is stable with about a 5 fs time step. To determine the correspondence between the UNRES time step and the time step of all-atom molecular dynamics, all-atom simulations with the AMBER 99 force field and explicit solvent and also with implicit solvent taken into account within the framework of the generalized Born/surface area (GBSA) model were carried out on the unblocked Ala(10) polypeptide. We found that the UNRES time scale is 4 times longer than that of all-atom MD simulations because the degrees of freedom corresponding to the fastest motions in UNRES are averaged out. When the reduction of the computational cost for evaluation of the UNRES energy function is also taken into account, UNRES (with hydration included implicitly in the side chain-side chain interaction potential) offers about at least a 4000-fold speed up of computations relative to all-atom simulations with explicit solvent and at least a 65-fold speed up relative to all-atom simulations with implicit solvent. To carry out an initial full-blown test of the UNRES/MD approach, we ran Berendsen-bath and Langevin dynamics simulations of the 46-residue B-domain of staphylococcal protein A. We were able to determine the folding temperature at which all trajectories converged to nativelike structures with both approaches. For comparison, we carried out ab initio folding simulations of this protein at the AMBER 99/GBSA level. The average CPU time for folding protein A by UNRES molecular dynamics was 30 min with a single Alpha processor, compared to about 152 h for all-atom simulations with implicit solvent. It can be concluded that the UNRES/MD approach will enable us to carry out microsecond and, possibly, millisecond simulations of protein folding and, consequently, of the folding process of proteins in real time. 相似文献
We review the coarse-grained UNited RESidue (UNRES) force field for the simulations of protein structure and dynamics, which is being developed in our laboratory over the last several years. UNRES is a physics-based force field, the prototype of which is defined as a potential of mean force of polypeptide chains in water, where all the degrees of freedom except the coordinates of α-carbon atoms and side-chain centers have been integrated out. We describe the initial implementation of UNRES to protein-structure prediction formulated as a search for the global minimum of the potential-energy function and its subsequent molecular dynamics and extensions of molecular-dynamics implementation, which enabled us to study protein-folding pathways and thermodynamics, as well as to reformulate the protein-structure prediction problem as a search for the conformational ensemble with the lowest free energy at temperatures below the folding-transition temperature. Applications of UNRES to study biological problems are also described. 相似文献
Here, we investigated the pathogenesis of primary biliary cirrhosis (PBC) by using 2D‐DIGE to analyze serological differences between anti‐mitochondrial antibody (AMA)‐positive and ‐negative PBC patients. The study comprised 30 patients with PBC; 20 AMA‐positive and ten AMA‐negative patients matched for age, sex , and pathological stage. A screening group (four AMA‐positive and four AMA‐negative patients) was used for 2D‐DIGE. Protein spots that were differently abundant between the two groups were identified via dye intensity and MS. Nine candidate proteins were identified from these spots. Western blotting was used to verify two of the identified proteins, serum amyloid P‐component (SAP) and vitronectin (VN). VN levels were significantly higher in the sera of AMA‐negative PBC patients (p < 0.01), whereas no significant difference was found between the two groups for SAP. To our knowledge, this is the first study to use serological comparative proteomics to explore differences between AMA‐positive and ‐negative PBC patients. VN levels were higher in AMA‐negative PBC patients, and this finding could be related to the more severe bile duct destruction observed in this group. 相似文献
Summary: This paper presents a computational study of phase separation‐phase ordering‐texturing in blends of polymer coils and rod‐like nematic liquid crystals under the presence of magnetic fields, using an extended version of the Matsuyama‐Evans‐Cates model (Phys. Rev. E 2000 , 61, 2977). This work demonstrates that demixing in these blends leads to droplet morphologies with tunable droplet shapes and director textures. In contrast to filled nematics, where solids are suspended in a nematic liquid crystal matrix, demixing in coil‐mesogenic rods blends leads to nematic emulsions, in which the deformable viscoelastic polymer drops are suspended in a nematic matrix. Under strong anchoring conditions, the imposition of a magnetic field leads to a director re‐orientation that due to strong anchoring produces a droplet shape change. Magnetic field‐induced shape transitions in these blends are shown to be second order with a finite critical field threshold that diverges as anchoring strength vanishes. A morphological‐texture diagram summarizes the magnetic field‐anchoring conditions that promote anisotropic shapes. This work presents additional material processing routes to design and control bi‐phasic morphologies in polymer‐liquid crystal blend.
Computed morphology phase diagram in terms of magnetic field strength ΛM and anchoring strength. ΛϕQ. 相似文献
A symplectic multiple-time-step (MTS) algorithm has been developed for the united-residue (UNRES) force field. In this algorithm, the slow-varying forces (which contain most of the long-range interactions and are, therefore, expensive to compute) are integrated with a larger time step, termed the basic time step, and the fast-varying forces are integrated with a shorter time step, which is an integral fraction of the basic time step. Based on the split operator formalism, the equations of motion were derived. Separation of the fast- and slow-varying forces leads to stable molecular dynamics with longer time steps. The algorithms were tested with the Ala(10) polypeptide chain and two versions of the UNRES force field: the current one in which the energy components accounting for the energetics of side-chain rotamers (U(rot)) can lead to numerically unstable forces and a modified one in which the the present U(rot) was replaced by a numerically stable expression which, at present, is parametrized only for polyalanine chains. With the modified UNRES potential, stable trajectories were obtained even when extending the basic time step to 15 fs and, with the original UNRES potentials, the basic time step is 1 fs. An adaptive multiple-time-step (A-MTS) algorithm is proposed to handle instabilities in the forces; in this method, the number of substeps in the basic time step varies depending on the change of the magnitude of the acceleration. With this algorithm, the basic time step is 1 fs but the number of substeps and, consequently, the computational cost are reduced with respect to the MTS algorithm. The use of the UNRES mesoscopic energy function and the algorithms derived in this work enables one to increase the simulation time period by several orders of magnitude compared to conventional atomic-resolution molecular dynamics approaches and, consequently, such an approach appears applicable to simulating protein-folding pathways, protein functional dynamics in a real molecular environment, and dynamical molecular recognition processes. 相似文献