Methane clathrate is an inclusion compound with methane molecules encaged in hydrogen-bonded water cavities. Understanding the formation and dissolution processes of methane clathrate is important for many scientific and industrial purposes. In this work methodologies are developed and refined to understand the thermodynamics of methane clathrate formation.

Proper sampling of methane clathrate configurations is challenging because there are many proton orientations that are almost degenerate. The timescale for interconversion among these orientations is longer than can be accessed by standard molecular dynamics techniques. In order to sample these proton orientations, an electrostatic switching procedure was developed. This technique can be applied to sample equilibrium configurations of ices, clathrate hydrates and glassy forms of water.

Non-equilibrium switching is an important part of the free energy determination procedure devised in this work. The efficiency of non-equilibrium simulations depends on the switching function. A technique was developed to obtain the optimal switching function during the simulation process by minimizing the production of irreversible work.

The free energy difference between two states vanishes at coexistence. Determining such a free energy difference typically relies on the cancellation of large numbers. Such a procedure is numerically challenging. In this work, the thermodynamic path between the two phases was chosen so that the cancellation of large numbers is avoided. This protocol was applied to calculate the melting point of ice Ih and methane clathrate. When coupled with classical nucleation theory, this protocol can be used to better understand the formation of methane clathrate.