Simulations

We conclude our investigation of bipolar disorder with molecular dynamics simulations of ADCY2, particularly its potential applicability to optogenetics. Specific attention will also be devoted to:

  • G-protein coupled receptors (GPCRs) that indirectly activate adenylate cyclase, the enzyme that generates the intracellular second messenger, cAMP.
  • Voltage-gated ion channels in nerve cells that open and close in response to binding of its specific ligand (such as a neurotransmitter) or by a change in the transmembrane electric potential.

neurotransmission

Molecular dynamics

Molecular dynamics simulates the macroscopic behaviour of a microscopic many-body system through the numerical integration of Newton’s equations of motion. It is a powerful computational method that allows us to follow and understand structure and dynamics in extreme detail, on a scale where the trajectories of individual atoms can be tracked. The macroscopic properties of the whole simulation system are expressed as functions of particle coordinates and momenta, which are computed along a trajectory generated by classical dynamics.

The time evolution of the system are driven by forces between particles, which in turn derive from a potential energy function V, also called the force field. The function defines the interaction terms between pairs of atoms and is typically divided into “bonded” and “non-bonded” interactions. The bonded interactions consist of bond stretching (Ebond), angle bending (Eangle) and dihedral angle deformation (Etorsion). Non-bonded interactions include electrostatic (Eelec) and van der Waals terms (Evdw). A set of atomic positions and velocities are then generated as a function of time, which evolve deterministically from an initial configuration according to the force field V.

force field

Methods

Conducting an ab initio MD simulation requires the following steps.

  • Obtaining a starting structure
  • Preparation of input data
  • Creating a simulation box
  • Adding solvent water
  • Adding ions
  • Energy minimization
  • Position restrained equilibration
  • Production runs
  • Trajectory analysis

Sources:

Electrostatic interactions and hydrogen bond dynamics in chloride pumping by halorhodopsin. Biochimica et Biophysica Acta

http://www.sciencedirect.com/science/article/pii/S0005272814006124

Molecular dynamics simulations of voltage-gated cation channels: insights on voltage-sensor domain function and modulation. Frontiers in Pharmacology

http://journal.frontiersin.org/Journal/10.3389/fphar.2012.00097/full

Homology modelling, molecular dynamics simulations and site-directed mutagenesis of histamine H2 receptors. PhD dissertation

http://epub.uni-regensburg.de/28729/1/PhD_Holzammer-2013.pdf

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