Protein force fields optimization

This review indicates that all-atom protein structure prediction with stochastic optimization methods becomes feasible with present-day computational resources. The fact that three proteins were reproducibly folded with different optimization methods to near-native conformation increases the confidence in the parameterization of our all-atom protein force field PFFOl. The... 

Best, R.B., Zhu, X., Shim, J., Lopes, P.E.M., Mittal, J., Feig, M., MacKerell, A.D. Optimization of the additive CHARMM All-atom protein force field Targeting improved sampling of the backbone (b, l/ and side-chain yl and y2 dihedral angles. J. Chem. Theory Comput. 8, 3257-3273 (2012)... 

Effective application of empirical force field based methodologies is based, in part, on the accuracy of the force field. The present article describes the functional forms of force fields used for the study of proteins. This is followed by information on the methods used for optimization of the force field parameters and how those parameters are tested. A brief conclusion includes a summary and an outlook of theoretical developments which may influence future protein force fields. The present article does not present a rigorous comparison of currently available force fields. Rather, it emphasizes the approaches used in the optimization and testing of protein force fields in order to allow the reader to select the most appropriate force field for the particular problem they are addressing. 

Protein force fields are necessarily complicated by the chemical nature of the amino acids comprising proteins. The chemical variability requires a wide number of model compounds be included during the parametrization process as target data. Furthermore, a significant number of test molecules should be selected these molecules should not be included with the model compounds in the original target data used in the optimization of the force field. This separation insures relatively unbiased testing of a force field to be performed. 

Proper parametrization of proteins requires the selection of appropriate model compounds for which adequate target data exist. As the peptide backbone C, O, N, H and C atoms are common to all amino acids selection of the appropriate model compounds for optimization of the peptide backbone parameters is central to the success of any protein force field. The most often used model compounds are NMA and ALAD, shown in Figure 1. Both structures contain the peptide bond capped by methyl groups. Earlier studies often employed formamide or acetamide as model compounds however, the free amino or aldehyde groups make them poor models for the peptide bond in proteins. Data available on NMA range from structural and vibrational data in both the gas and conden.sed pha.ses to crystal structures, pure solvent properties and heats... 

OPTS (Optim i/.ed Potentials for Liquid Simulations) is based on a force field developed by the research group of Bill Jorgensen now at Yale University and previously at Purdue University. Like AMBER, the OPLS force field is designed for calculations on proteins an d nucleic acids. It in troduces non bonded in leraclion parameters that have been carefully developed from extensive Monte Carlo liquid sim u lation s of small molecules. These n on-bonded interactions have been added to the bonding interactions of AMBER to produce a new force field that is expected to be better than AMBER at describing simulations w here the solvent isexplic-... 

ChemSketch has some special-purpose building functions. The peptide builder creates a line structure from the protein sequence defined with the typical three-letter abbreviations. The carbohydrate builder creates a structure from a text string description of the molecule. The nucleic acid builder creates a structure from the typical one-letter abbreviations. There is a function to clean up the shape of the structure (i.e., make bond lengths equivalent). There is also a three-dimensional optimization routine, which uses a proprietary modification of the CHARMM force field. It is possible to set the molecule line drawing mode to obey the conventions of several different publishers. 

Krieger E, Darden T, Nabuurs SB, Finkelstein A, Vriend G. Making optimal use of empirical energy functions force-field parameterization in crystal space. Proteins 2004 57 678-83. 

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