Table 1.

Glossary of terms.

Term	Definition
Bayesian inference	Statistical method in which a prior probability distribution is combined with a likelihood function informed by external (e.g. experimental) evidence to provide an updated (or posterior) probability estimate
Collective variable	A mathematical function of particle (e.g. atom) positions used as a reaction coordinate for progress along a free energy surface
Convergence	Approach of a given variable towards a steady state value; it is often used with reference to a statistical estimate performed along a molecular dynamics simulation: as the trajectory length increases, the average properties of the system can be estimated with increasing accuracy. When uncertainties fall below a given threshold, the calculation is considered converged
Cryo-electron microscopy (EM)	Structural biology technique based on the transmission of an electron beam through frozen purified macromolecules, potentially yielding atomic-resolution data for generally large (>100 kD) complexes
Electron paramagentic resonance (EPR)	Spectroscopic tool enabling measurement of distances, conformational populations, and/or local dynamics of macromolecules labeled with small spin probes
Electronic structure problem	The problem of finding the wavefunctions that solve the time-independent Schrödinger equation for a given configuration of atomic nuclei
Enhanced sampling	Methods that improve the ability of molecular dynamics simulations to sample rare events and regions of a free energy landscape of low probability
Flooding simulations	Molecular dynamics protocol used to identify putative binding sites in proteins. It uses a large concentration of ligands in the aqueous portion of the simulated system so that the probability of observing binding events is greatly increased
Fluorescence	Spectroscopic tool, applicable on scales as small as individual molecules, yielding information such as domain distances, conformational populations, and interconversion rates
Force field	Set of empirical parameters used to approximate the potential energy surface of a system; may treat electrostatics through the use of point charges only or by complementing the latter with inducible dipoles (polarizable force field)
Free energy landscape	Multidimensional description of a system’s Gibbs free energy using, as variables, a set of reaction coordinates
Free energy perturbation	Method to calculate the free energy change upon chemical modification of a system, e.g. single residue mutation, through a series of molecular dynamics simulations
Gating current	Transmembrane current upon gating of a voltage-sensitive proteins, arising not from solvent ion flow, but from relative movement of charges or dipoles; in voltage-gated ion channels, the charge is carried by basic residues located in the voltage sensor domain
Markov model	A stochastic model in which the defining property is that probabilities of transition to a subsequent state depend only on the current state, and not on the history of previous events
Metadynamics	A type of enhanced sampling technique that applies a time-dependent repulsive bias potential to discourage the system from occupying repeatedly the same configuration
Molecular dynamics	Computational approach to calculate the trajectory of a system of interacting particles (usually atoms). Forces can be derived from empirical formulas (classical molecular dynamics) or from solving Schrodinger equation (ab initio molecular dynamics)
Nuclear magentic resonance (NMR)	Spectroscopic tool based on the varying magnetic fields around atoms in a molecule, potentially yielding atomic-resolution data including dynamics of small (<30 kD) isotopically labeled proteins
Patch clamp	Electrophysiology technique in which a micropipette is sealed to a piece of cell membrane, capturing the electrical activity of one or several membrane proteins
Planar lipid bilayer recording	Electrophysiology technique in which membrane proteins are reconstituted in small patches of synthetic bilayer in a recording cuvette
Polarizability	Ability of a charge distribution to reorganize in response to an external electrostatic field by forming instantaneous dipoles. Atomic polarizability is a crucial component of intermolecular interactions and is included (in an approximate fashion) in some modern force fields (polarizable force fields)
Potential energy surface	Multidimensional description of a system’s energy based on the positions of its nuclei
Probability density	Mathematical function describing the relative likelihood for a variable to fall in a given range; in the molecular context it describes the probability that atoms adopt any given conformation
Quantum mechanics	Description of the positions and momenta of (sub)atomic particles based on Schrödinger equation
Simulated annealing	Molecular dynamics protocol used to find the global energy minimum. It consists in gradually decreasing the temperature of a simulation from very high to very low values. The high temperature phase promotes the crossing of free energy barriers, while the low temperature one samples the states with lowest energy
Temperature replica exchange	Molecular dynamics protocol consisting in a set of molecular dynamics simulations at different temperatures; periodic exchange of configurations across replicas results in a more efficient exploration a free energy landscape compared to a traditional molecular dynamics run
Two-electrode voltage-clamp	Electrophysiology technique in which a large cell is impaled with two sharp microelectrodes, one to record membrane potential, the other to inject current
Umbrella sampling	A type of enhanced sampling technique that applies a harmonic bias potential to a collective variable to promote the sampling of configurations with low probability of occurrence
X-ray crystallography	Structural biology technique based on the diffraction of X-rays by symmetrically repeating atoms in a crystal, potentially yielding sub-Å resolution data with few size limitations