A solvation term based on the solvent accessible surface area (SASA) is combined with the CHARMM polar hydrogen force field for the efficient simulation of peptides and small proteins in aqueous solution. Only two atomic solvation parameters are used: one is negative for favoring the direct solvation of polar groups and the other positive for taking into account the hydrophobic effect on apolar groups. To approximate the water screening effects on the intrasolute electrostatic interactions, a distance-dependent dielectric function is used and ionic side chains are neutralized. The use of an analytical approximation of the SASA renders the model extremely efficient (i.e., only about 50% slower than in vacuo simulations). The limitations and range of applicability of the SASA model are assessed by simulations of proteins and structured peptides. For the latter, the present study and results reported elsewhere show that with the SASA model it is possible to sample a significant amount of folding/unfolding transitions, which permit the study of the thermodynamics and kinetics of folding at an atomic level of detail.

Articles you may be interested inStudy on the conformational equilibrium of the alanine dipeptide in water solution by using the averaged solvent electrostatic potential from molecular dynamics methodology J. Chem. Phys. 135, 194502 (2011); 10.1063/1.3658857 Free energy of conformational transition paths in biomolecules: The string method and its application to myosin VI J. Chem. Phys. 134, 085103 (2011); 10.1063/1.3544209An application of coupled reference interaction site model/molecular dynamics to the conformational analysis of the alanine dipeptide Optimal free energy paths ͑OFEPs͒ for conformational transitions are parallel to the mean force at every nonstationary point of the free energy landscape. In contrast to adiabatic paths, which are parallel to the force, OFEPs include the effect of entropy and are relevant even for systems with diffusive degrees of freedom. In this study the OFEPs are computed for the alanine dipeptide in solution. The potential of mean force is calculated and an effective potential is derived that is used to obtain the paths with a minimization based algorithm. The comparison of the calculated paths with the adiabatic paths in vacuo shows the influence of the environment on conformational transitions. The dynamics of the alanine dipeptide in water are more complex, since there are more minima and the barriers are lower. Two simpler methods for the calculation of reaction pathways in solution are evaluated by comparing their results with the OFEPs. In the first method the mean electrostatic field of the water is approximated by an analytical continuum model. The obtained paths show qualitative agreement with the OFEPs and the height of the barriers are similar. Targeted molecular dynamics ͑TMD͒, the second approach, constrains the distance to a target conformation to accelerate the transition. In the general case, however, it is difficult to assess the physical significance of the obtained paths. Changing the initial conditions by assigning different velocities leads to different solutions for the conformational transition. Furthermore, it is shown that by performing the simulations with different reaction coordinates or in opposite directions different pathways are preferred. This result can be explained by the structure of the free energy landscape around the initial conformations. In a first approximation the physical significance of different pathways is assumed to depend mainly on the free energy at the highest saddle point. In the literature the total energy of the system has often been used to estimate the position and the height of the energy barriers in the path. By comparing the total energy with the calculated free energy it is shown that the former largely overestimates the height of the barriers. Furthermore, the positions of the maxima of the total energy do not coincide with the free energy barriers. Simple approximations to the free energy lead to good quantitative agreement.

The efficient evaluation of electrostatic energies of macromolecules in aqueous solutions is useful for many problems in theoretical structural biology. A continuum method based on the generalized Born (GB) approximation is implemented here. It is shown that the choice of the dielectric discontinuity surface is critical for obtaining correct electrostatic energies of molecules in solution. In addition, it is demonstrated that an electrostatic model validated on solvation energies (vacuum to water transfer) might not be appropriate for energies in solution and might not yield correct energy ranking of ligand/protein complexes. The agreement between the GB approach and the finite difference solution of the Poisson equation is shown to be very good for both the molecular and the solvent accessible surface. The discrepancies between the GB and the finite difference approach are much lower than the ones due to the use of different surfaces.

A new method is presented for docking molecular fragments to a rigid protein with evaluation of the binding energy. Polar fragments are docked with at least one hydrogen bond with the protein while apolar fragments are positioned in the hydrophobic pockets. The electrostatic contribution to the binding energy, which consists of screened intermolecular energy and protein and fragment desolvation terms, is evaluated efficiently by a numerical approach based on the continuum dielectric approximation. The latter is also used to predetermine the hydrophobic pockets of the protein by rolling a low dielectric sphere over the protein surface and calculating the electrostatic desolvation of the protein and van der Waals interaction energy. The method was implemented in the program SEED (solvation energy for exhaustive docking). The SEED continuum electrostatic approach has been successfully validated by a comparison with finite difference solutions of the Poisson equation for more than 2,500 complexes of small molecules with thrombin and the monomer of HIV-1 aspartic proteinase. The fragments docked by SEED in the active site of thrombin reproduce the structural features of the interaction patterns between known inhibitors and thrombin. Moreover, the combinatorial connection of these fragments yields a number of compounds that are very similar to potent inhibitors of thrombin. Proteins 1999;37:88-105.

The folding of an R-helix and a β-hairpin was studied by 862 molecular dynamics simulations with an implicit solvation model that allowed sampling of a total of 4 µs. The average effective energy is rather flat for conformations having less than about 50% of the folded state contacts formed, except for the R-helix at very high temperatures. For both peptides there is a smooth decrease of the effective energy close to the folded state. The free energy landscape shows that the helix-coil transition is not first order, while the β-hairpin has one or two minima, depending on the temperature. At low temperature (T < 1.1T m ) there is an increase in the folding rate with increasing temperature as expected from an activation energy limited process. At higher temperatures the rate decreases for both peptides which is consistent with an activation entropy dominated process. The unfolding rate, by contrast, shows an Arrhenius-like behavior; i.e., it increases monotonously with temperature. The β-hairpin peptide folds about 30 times slower than the R-helix peptide at 300 K. Multiple folding pathways are present for the R-helix, whereas the β-hairpin initiates folding mainly at the β-turn.