Calculation of conformational transitions and barriers in solvated systems: Application to the alanine dipeptide in water

Optimal free energy paths (OFEPs) for conformational transitions are parall el to the mean force at every nonstationary point of the free energy landsc ape. In contrast to adiabatic paths, which are parallel to the force, OFEPs include the effect of entropy and are relevant even for systems with diffu sive degrees of freedom. In this study the OFEPs are computed for the alani ne 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 mini mization based algorithm. The comparison of the calculated paths with the a diabatic paths in vacuo shows the influence of the environment on conformat ional transitions. The dynamics of the alanine dipeptide in water are more complex, since there are more minima and the barriers are lower. Two simple r methods for the calculation of reaction pathways in solution are evaluate d by comparing their results with the OFEPs. In the first method the mean e lectrostatic 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 (TMD), the second approach, constrains the distance to a target conformation to accel erate the transition. In the general case, however, it is difficult to asse ss the physical significance of the obtained paths. Changing the initial co nditions 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 directi ons different pathways are preferred. This result can be explained by the s tructure of the free energy landscape around the initial conformations. In a first approximation the physical significance of different pathways is as sumed to depend mainly on the free energy at the highest saddle point. In t he literature the total energy of the system has often been used to estimat e the position and the height of the energy barriers in the path. By compar ing the total energy with the calculated free energy it is shown that the f ormer largely overestimates the height of the barriers. Furthermore, the po sitions of the maxima of the total energy do not coincide with the free ene rgy barriers. Simple approximations to the free energy lead to good quantit ative agreement. (C) 1999 American Institute of Physics. [S0021-9606(99)502 04-3].