Protein folding force field

The most ambitious approaches to the protein folding problem attempt to solve it from firs principles (ab initio). As such, the problem is to explore the coirformational space of th molecule in order to identify the most appropriate structure. The total number of possibl conformations is invariably very large and so it is usual to try to find only the very lowes energy structure(s). Some form of empirical force field is usually used, often augmente with a solvation term (see Section 11.12). The global minimum in the energy function i assumed to correspond to the naturally occurring structure of the molecule. 

Folding energy and catalysis, 227 Force field approach, consistent 113 Free energy, 43,47 of activation, 87-90, 92-93, 93, 138 of charging processes, 82 convergence of calculations of, 81 in proteins, SCAAS model for, 126 of reaction, 90... 

The resonance-mediated coupling mechanisms described above involve subtle quantal intramolecular/intermolecular donor-acceptor effects that tend to be inadequately described by current-generation empirical potentials. Simulations based on these potentials are therefore likely to be inherently defective for describing realistic folding processes in proteins. However, approximations such as those illustrated in Example 5.8 may ultimately make it feasible to incorporate additional resonance-mediated effects into empirical force fields of tractable form. 

It is, however, important to note what might be accomplished if the growth rate calculated above can be continued for another 10-20 years. If this happens, simulations on proteins with 100-200 residues can be expected to reach into the millisecond domain, and simulations covering a full second would be attainable within about twenty years. Recent demonstrations of the accuracy of modern molecular force fields [62,63] hold the promise that unbiased molecular dynamics simulations could follow the folding process all the way from the completely unfolded state to the native state, a truly exciting prospect. 

Summary. We recently developed an all-atom free energy force field (PFFOl) for protein structure prediction with stochastic optimization methods. We demonstrated that PFFOl correctly predicts the native conformation of several proteins as the global optimum of the free energy surface. Here we review recent folding studies, which permitted the reproducible all-atom folding of the 20 amino-acid trp-cage protein, the 40-amino acid three-helix HIV accessory protein and the sixty amino acid bacterial ribosomal protein L20 with a variety of stochastic optimization methods. These results demonstrate that all-atom protein folding can be achieved with present day computational resources for proteins of moderate size. 

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... 

T. Herges and W. Wenzel. Reproducible in-silico folding of a three-helix protein in a transferable all-atom force field. Physical Review Letters (in press), http //www.arXiv.org physics/0310146, 2004. 

A. Schug, T. Herges, and W. Wenzel. All-atom folding of the trp-cage protein in an all-atom force field. Europhyics Lett., 67 307-313, 2004. 

In conclusion, it appears that the majority of the most modem force fields do well in predicting structural and dynamical properties within wells on their respective PESs. However, their performance for non-equilibrium properties, such as timescales for conformational interconversion, protein folding, etc., have not yet been fully validated. With the increasing speed of both computational hardware and dynamics algorithms, it should be possible to address this question in the near future. 

Standard molecular mechanics (MM) force fields have been developed that provide a good description of protein structure and dynamics,21 but they cannot be used to model chemical reactions. Molecular dynamics simulations are very important in simulations of protein folding and unfolding,22 an area in which they complement experiments and aid in interpretation of experimental data.23 Molecular dynamics simulations are also important in drug design applications,24 and particularly in studies of protein conformational changes,25,26 simulations of the structure and function of ion channels and other membrane proteins,27-29 and in studies of biological macromolecular assemblies such as F-l-ATPase.30... 

The final example is the results of the applications of REMD simulations to the folding of a small protein, namely, the Bl domain of streptococcal protein G [164]. The simulations were performed on the Earth Simulator. Protein G consists of 56 amino acids, and the total number of atoms in the protein is 855. For the force fields, we used OPLS-AA/L [165] for the protein molecule and TIP3P [143] for water molecules. We first performed a REMD simulation of protein G in vacuum with 96 replicas. The initial conformation of the REMD simulation was a fully extended one. We then solvated one of the obtained... 

---