A generalized Langevin dynamics approach to model solvent dynamics effects on proteins via a solvent-accessible surface. The carboxypeptidase A inhibitor protein as a model

Abstract.

A generalized Langevin dynamics (GLD) scheme is derived for (bio)macromolecules having internal structure, arbitrary shapes and a size larger than solvent molecules (i.e. proteins). The concept of solvent-accessible surface area (SASA) is used to incorporate solvent effects via external forces thereby avoiding its explicit molecular representation. A simulation algorithm is implemented in the GROMOS molecular dynamics (MD) program including random forces and memory effects, while solvation effects enter via derivatives of the surface area. The potato carboxypeptidase inhibitor (PCI), a small protein, is used to numerically test the approach. This molecule has N- and C-terminal tails whose structure and fluctuations are solvent dependent. A 1-ns MD trajectory was analyzed in depth. X-ray and NMR structures are used in conjunction with MD simulations with and without explicit solvent to gauge the quality of the results. All the analyses showed that the GLD simulation approached the results obtained for the MD simulation with explicit simple-point-charge-model water molecules. The SASAs of the polar atoms show a natural exposure towards the solvent direction. A FLS solvent simulation was completed in order to sense memory effects. The approach and results presented here could be of great value for developing alternatives to the use of explicit solvent molecules in the MD simulation of proteins, expanding its use and the time-scale explored.