Gaussian Accelerated MD

A class of molecular dynamics techniques that apply external biases to accelerate the exploration of a system's free energy landscape, enabling the observation of rare events within computationally feasible timescales. Unlike standard MD, which can be trapped in local minima for microseconds, enhanced sampling methods systematically overcome high energy barriers.

• GaMD is a specific type of enhanced sampling that does not require predefined collective variables
• Other methods include Metadynamics, Replica Exchange MD, and Umbrella Sampling
• Critical for studying protein folding, ligand binding, and conformational changes

An enhanced sampling method that discourages revisiting previously explored states by depositing a history-dependent Gaussian bias potential along a set of predefined collective variables, effectively filling free energy minima. As the simulation progresses, the accumulated bias forces the system to escape metastable states.

• Requires careful selection of collective variables (CVs) that capture the slow degrees of freedom
• Well-tempered metadynamics converges the bias to an estimate of the free energy surface
• Contrasts with GaMD, which boosts the entire potential energy surface without CV specification

A parallel tempering technique that runs multiple non-interacting simulations at different temperatures or Hamiltonians and periodically attempts to exchange configurations between them to overcome energy barriers. High-temperature replicas cross barriers easily, while low-temperature replicas provide detailed conformational sampling.

• Also known as parallel tempering
• Hamiltonian replica exchange varies the potential energy surface rather than temperature
• Computationally expensive due to the requirement of many simultaneous replicas
• GaMD achieves similar barrier crossing with a single trajectory

A low-dimensional function of a system's atomic coordinates that describes the essential slow degrees of freedom governing a specific process, such as a distance, angle, or coordination number. CVs are the fundamental input for many enhanced sampling methods but are deliberately avoided in GaMD.

• Common CVs: RMSD, radius of gyration, number of hydrogen bonds, dihedral angles
• Poor CV selection leads to incomplete sampling and hysteresis
• GaMD's key innovation is eliminating the need for CV predefinition by boosting the total potential and dihedral energies directly

A multidimensional surface describing the thermodynamic stability of a system as a function of its configurational coordinates. The minima represent stable states, while the barriers between them determine transition kinetics. GaMD's primary purpose is to enable efficient exploration and reconstruction of this landscape.

• Defined by the potential of mean force (PMF) along chosen coordinates
• Accurate reconstruction requires proper reweighting of the biased GaMD trajectory
• Applications include calculating protein-ligand binding free energies and identifying cryptic allosteric pockets

A kinetic network model that discretizes a molecular system's phase space into metastable states and estimates a transition probability matrix to describe long-timescale dynamics from many short simulations. MSMs are complementary to GaMD, as GaMD can efficiently generate the diverse starting configurations needed to seed MSM construction.

• Built from time-lagged independent component analysis (tICA) for dimensionality reduction
• Enables calculation of mean first passage times and dominant transition pathways
• GaMD-accelerated trajectories can dramatically reduce the aggregate simulation time required for converged MSMs