Real chemical systems often require multiple dimensions to capture relevant anharmonicity changes in the potential. A practical approach is to define N d descriptors d i (R), functions of atomic coordinates R, which serve as the basis for constructing the CV. The procedure remains similar to the 1D case: after defining these descriptors, the system is briefly sampled at a given temperature, generating an N ddimensional distribution. However, extending skewness FIG. . Schematic representation of the Loxodynamics approach. The upper panel compares a simple one-dimensional double-well potential (solid black line) with a harmonic potential (dashed line) near the local minimum on the left. Hypothetical sampling of these potentials would yield two distinct probability distributions: the harmonic potential produces a symmetric Gaussian-like distribution, while the double-well potential results in a left-modal distribution with positive skewness. Loxodynamics leverages this skewness to determine the optimal biasing direction. The lower panel illustrates how successive sampling along the double-well potential is achieved by applying a bias in the form of a half-harmonic wall, oriented against the positive skewness, thereby steering the system toward the right metastable state.