Protein Modeling Folding Unfolding Dynamics

One of the major objectives of the physical chemistry studies in water and biomolecules is to fully reproduce the experimentally observed folding/ unfolding behavior of a typical model protein in water by means of molecular simulation. However, the all-atom molecular dynamics (MD) simulation of the folding of a protein from the fully unfolded state to the native structure remains computationally intractable when the size of the target protein is larger than 100 residues and when simulation is carried out with explicit water molecules (i.e., when complete, contextualized simulation is attempted) [1-3]. 

Given a model of the protein, one is left to define a criterion for the folded state of the protein. There is much debate over whether the native folded state of the protein represents a thermodynamically dominant state or a kinetically trapped state. It may be that there are examples of both types. To determine the structure of a kinetically determined folded state, it must be possible to simulate the folding of the protein from its unfolded state. In real time, this process typically takes on the order of milliseconds to seconds and is beyond the realm of current molecular dynamics simulation. If the native state is thermodynamically dominant then, if the equilibrium ensemble of protein structures can be simulated, the native state could presumably be recognized from the set of structures at equilibrium. Because of computational limitations, it is not possible to generate an ensemble of structures that adequately represents the equilibrium ensemble for even the smallest globular proteins. A simplifying assumption is necessary. 

Three theory papers are also included. Determinants of the Polyproline II Helix from Modeling Studies by Creamer and Campbell reexamines and extends an earlier hypothesis about Pn and its determinants. Hydration Theory for Molecular Biophysics by Paulaitis and Pratt discusses the crucial role of water in both folded and unfolded proteins. Unfolded State of Peptides by Daura et al. focuses on the unfolded state of peptides studied primarily by molecular dynamics. 

For folded proteins, relaxation data are commonly interpreted within the framework of the model-free formalism, in which the dynamics are described by an overall rotational correlation time rm, an internal correlation time xe, and an order parameter. S 2 describing the amplitude of the internal motions (Lipari and Szabo, 1982a,b). Model-free analysis is popular because it describes molecular motions in terms of a set of intuitive physical parameters. However, the underlying assumptions of model-free analysis—that the molecule tumbles with a single isotropic correlation time and that internal motions are very much faster than overall tumbling—are of questionable validity for unfolded or partly folded proteins. Nevertheless, qualitative insights into the dynamics of unfolded states can be obtained by model-free analysis (Alexandrescu and Shortle, 1994 Buck etal., 1996 Farrow etal., 1995a). An extension of the model-free analysis to incorporate a spectral density function that assumes a distribution of correlation times on the nanosecond time scale has recently been reported (Buevich et al., 2001 Buevich and Baum, 1999) and better fits the experimental 15N relaxation data for an unfolded protein than does the conventional model-free approach. 

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... 

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