Force ECEPP

Empirical conformational energy program for peptides (ECEPP) is the name of both a computer program and the force field implemented in that program. This is one of the earlier peptide force fields that has seen less use with the introduction of improved methods. It uses three valence terms that are fixed, a van der Waals term, and an electrostatic term. 

Many technical limitations remain to be overcome before ligand design becomes reliable and routine. Many deficiencies in molecular mechanics previously cited remain that limit reliability. Adequate modeling of electrostatics remains elusive in many experimental systems of interest such as membranes. Newer derivations of force fields, such as MM3 (27, 296 and references therein), CHARMM (297, 298), AMBER/OPLS (157), ECEPP (299), and others (156, 300), are attempting to more accurately represent the experimental data, whereas others include a broader spec-... 

We extended the use of our program Anneal-Conformer and the Amber force field for conformation searching of peptides [5]. We were also able to efficiently locate several new families of active conformations of Met-enkephalin [6]. Similar studies of Met-enkephalin Kawai [7] on a simplified ECEPP energy surface also demonstrated the efficiency of simulated annealing. 

Fig. 6. Low-energy structure of the 36-residue chicken villin headpiece sub-domain HP-36. On the left the structure determined in NMR experiments is shown. The right panel shows the lowest-energy configuration found in a feedback-optimized allatom parallel tempering simulation using the ECEPP/2 force field and an implicit solvent model. The root-mean square deviation of this structure to the structure on the left is Rrmsd = 3.8 A...

Applying an all-atom parallel tempering simulation of the protein HP-36 in the ECEPP/2 force field [33] using an implicit solvent model [34] the authors of [27] have measured the diffusion of labeled replicas in temperature space. The simulated temperature interval is chosen such that at the lowest temperature = 250 K the protein is in a folded state and the highest temperature T ax = 1000 K ensures that the protein can fully unfold for the simulated force field. The measured local diffusivity for the random walk between these two extremal temperatures is shown in Fig. 7. A very strong modulation of the local diffusivity is found along the temperature. Note the logarithmic scale of the ordinate. The pronounced minimum of the local diffusivity around T 500 K points to a severe bottleneck in the simulation which by measurements of the specific heat has been identified as the helix-coil... 

An optimized temperature set for the parallel tempering simulation of HP-36 in the ECEPP/2 force field can then be found by feeding back the local diffusivity appl3ung the algorithm outlined above. Results for a temperature set with 20 temperature points are illustrated in Fig. 8 for an initial temperature set which similar to a geometric progression concentrates temperature points at low temperatures [27]. After the feedback temperature points concentrate around the bottleneck of the simulation, primarily around the helix-coil transition at T 500 K and in the temperature regime 350 K < T < 490 K below the transition where a shoulder in the local diffusivity was found. 

Part of simulation ECEPP/2 vdW + electrostatic, hydrogen bonds, torsional potential e = 2 united-atom + polar hydrogens harmonic force on N, Ca, C, O atoms of terminal residues on x-ray positions... 

By the early 1970s, molecular mechanics computer programs such as MMI and MM2 were available, running on the IBM 360. For proteins, ECEPP was developed by Harold A. Scheraga. - Countering the molecular mechanics approach, Michael J. S. Dewar modified John A. Pople s (complete) neglect-of-differential-overlap semiempirical quantum mechanical method (CNDO/2) to calculate quantities such as conformational stability and heats of formation. Such programs (MNDO) were necessarily slower than the empirical force field methods such as MM2 and ECEPP but still had fewer parameters and could account for the effects of polarization in aromatic systems. 

In order to appreciate the differences in the atomic charges obtained for the same amide fragment (NHCOC H ) of peptides and proteins a number of point charge sets were compared by Rullman [104] (Table 1). The charges used in various empirical force fields come from different quantum chemical calculations. For example, the ECEPP [105] and CHARMM [106] charges were determined on the basis of CNDO/2 studies, while the AMBER [107] and OPES [108] charges came from approximately scaled ab initio SCF calculations. Rullman and van Duijnen [109] used the dipole moment conserving population analysis [100] for the HF SCF wave function with the Mehler-Paul basis set [110]. 

For a significant portion of this work, the ECEPP/3 (Empirical Conformational Energy Program for Peptides) [38] potential model is utilized. In this force field, it is assumed that the covalent bond lengths and bond angles are fixed at their equilibrium values. Then, the conformation is only a function of... 

The OONS parameter set has been specifically developed to supplement the ECEPP/2 force field [65]. These parameters were derived by a least squares... 

A detailed modeling approach is proposed by using the ECEPP/3 force held [38]. When considering an unconstrained minimization, this approach provides the following objective function ... 

The algorithmic steps for the constrained aBB approach can be generalized to any force field model or routine for solving constrained optimization problems. Here, the otBB approach is interfaced with PACK [74] and NPSOL [28]. PACK is used to transform to and from Cartesian and internal coordinate systems, as well as to obtain function and gradient contributions for the ECEPP/3 force field and the distance constraint equations. NPSOL is a local nonlinear optimization solver that is used to locally solve the constrained upper and lower bounding problems in each subdomain. 

Recently, a novel decomposition-based approach has been proposed for predicting binding site structures in the MHC 11 HLA-DRl protein [183]. In this approach, existing MHC n crystal structures are used to predict the binding site conformations of other MHC n molecules. The approach uses the detailed potential energy force field ECEPP/3 and an area-based solvation method. A... 

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