Development of molecular simulation methods to accurately represent protein-surface interactions: The effect of pressure and its determination for a system with constrained atoms.

When performing molecular dynamics simulations for a system with constrained (fixed) atoms, traditional isobaric algorithms (e.g., NPT simulation) often cannot be used. In addition, the calculation of the internal pressure of a system with fixed atoms may be highly inaccurate due to the nonphysical nature of the atomic constraints and difficulties in accurately defining the volume occupied by the unconstrained atoms in the system. The inability to properly set and control pressure can result in substantial problems for the accurate simulation of condensed-phase systems if the behavior of the system (e.g., peptide/protein adsorption) is sensitive to pressure. To address this issue, the authors have developed an approach to accurately determine the internal pressure for a system with constrained atoms. As the first step in this method, a periodically extendable portion of the mobile phase of the constrained system (e.g., the solvent atoms) is used to create a separate unconstrained system for which the pressure can be accurately calculated. This model system is then used to create a pressure calibration plot for an intensive local effective virial parameter for a small volume cross section or "slab" of the system. Using this calibration plot, the pressure of the constrained system can then be determined by calculating the virial parameter for a similarly sized slab of mobile atoms. In this article, the authors present the development of this method and demonstrate its application using the CHARMM molecular simulation program to characterize the adsorption behavior of a peptide in explicit water on a hydrophobic surface whose lattice spacing is maintained with atomic constraints. The free energy of adsorption for this system is shown to be dramatically influenced by pressure, thus emphasizing the importance of properly maintaining the pressure of the system for the accurate simulation of protein-surface interactions.