Molecular modeling protein force fields

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... 

To perform the design of new molecules based on the approaches described above, powerful computer-aided tools are required. These include molecular modeling tools for visualization and analysis, extraction of 3D structures from databases, construction of 3D models using force fields [77-79] and molecular dynamics methods, docking of 3D models to protein cavities. These methods have been documented in detail in the previous volumes of this series and in a number of recent review articles [80-87]. These will therefore only be discussed in the context of the case studies presented in this volume. 

A step forward along the route to the correct modelling of the spectroscopy and photochemical reactivity of photoreactive proteins is represented by the implementation of a Quantum Mechanics/Molecular Mechanics (QM/MM) computational strategy based on a suitable QM part coupled with a protein force field such as AMBER [34] (or CHARMM [35]). Very recently a CASPT2//CASSCF/AMBER method for rhodopsin has been implemented in our laboratory [36,37] within the QM/MM hnk-atom scheme [38]. Special care has been taken in the parametrization of the protonated Schiff base linkage region that describes the dehcate border region between the MM (the protein)... 

Given that our model system was smaller than the protein employed in the force-clamp AI experiments, the very first thing that needs to be proven is that the observed force-induced conformational rearrangement in the diethyl disulfide molecule can also take place in the protein and, thus, that the mechanism extracted from this model is responsible for the experimental findings reported for the protein. Force-field molecular dynamics simulations carried out on the same system used in... 

Guvench O, MacKerell AD (2008) Comparison of protein force fields for molecular dynamics simulations. In Kukol A (ed) Molecular modeling of proteins. Hiunana Press, New York... 

The rhodopsin protein problem An all-atom rhodopsin protein was set in a solvated lipid bilayer described via the Chemistry at Harvard Molecular Mechanics (CHARMM) force field. Long-range coulomb interactions were described via the particle-particle mesh. SHAKE constraints were applied to the system for the definitions of the force field and constraints. Further, the model consisted of counter ions with a reduced amount of water the effect was to have a total system with 32,000 atoms that was simulated for 100 time steps. This simulation was performed at a constant pressure and temperature with an LJ force cutoff of 10.0 Angstroms. In this problem, the total number of neighbors per atom was 440 within this force cutoff More information about the benchmark problem can be found at http //lammps.sandia.gOv/bench.html rhodo... 

Aqueous Interfaces Biomembranes Modeling CHAR-MM The Energy Function and Its Parameterization Hydrophobic Effect Molecular Dynamics Studies of Lipid Bilayers Molecular Dynamics Techniques and Applications to Proteins Permeation of Lipid Membranes Molecular Dynamics Simulations Protein Force Fields. 

As computational power advanced and became more accessible, so did the detail incorporated into the protein models. By 1977, work had moved toward united atom representations of proteins and the use of molecular mechanics to characterize the native state dynamics of BPTI in vacuo with no water included except for four crystalline waters.The empirical energy function used in this first protein MD simulation forms the basis of today s protein force fields. 

Conformational Adjustments The conformations of protein and ligand in the free state may differ from those in the complex. The conformation in the complex may be different from the most stable conformation in solution, and/or a broader range of conformations may be sampled in solution than in the complex. In the former case, the required adjustment raises the energy, in the latter it lowers the entropy in either case this effect favors the dissociated state (although exceptional instances in which the flexibility increases as a result of complex formation seem possible). With current models based on two-body potentials (but not with force fields based on polarizable atoms, currently under development), separate intra-molecular energies of protein and ligand in the complex are, in fact, definable. However, it is impossible to assign separate entropies to the two parts of the complex. 

In order to represent 3D molecular models it is necessary to supply structure files with 3D information (e.g., pdb, xyz, df, mol, etc.. If structures from a structure editor are used directly, the files do not normally include 3D data. Indusion of such data can be achieved only via 3D structure generators, force-field calculations, etc. 3D structures can then be represented in various display modes, e.g., wire frame, balls and sticks, space-filling (see Section 2.11). Proteins are visualized by various representations of helices, / -strains, or tertiary structures. An additional feature is the ability to color the atoms according to subunits, temperature, or chain types. During all such operations the molecule can be interactively moved, rotated, or zoomed by the user. 

Assisted model building with energy refinement (AMBER) is the name of both a force field and a molecular mechanics program. It was parameterized specifically for proteins and nucleic acids. AMBER uses only five bonding and nonbonding terms along with a sophisticated electrostatic treatment. No cross terms are included. Results are very good for proteins and nucleic acids, but can be somewhat erratic for other systems. 

In computational chemistry it can be very useful to have a generic model that you can apply to any situation. Even if less accurate, such a computational tool is very useful for comparing results between molecules and certainly lowers the level of pain in using a model from one that almost always fails. The MM+ force field is meant to apply to general organic chemistry more than the other force fields of HyperChem, which really focus on proteins and nucleic acids. HyperChem includes a default scheme such that when MM+ fails to find a force constant (more generally, force field parameter), HyperChem substitutes a default value. This occurs universally with the periodic table so all conceivable molecules will allow computations. Whether or not the results of such a calculation are realistic can only be determined by close examination of the default parameters and the particular molecular situation. ... 

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