Small molecule force field parametrization for atomistic Molecular Dynamics simulations ======================================================================================== Overview --------- This **use case** aims to illustrate the process of **parameterizing a small molecule**, to be used in a Molecular Dynamics simulation, step by step. The particular example used is the **Imipramine molecule** (PDB code `IXX `_, DrugBank code `DB00458 `_). **Imipramine** is a tricyclic antidepressant (TCA) which is used mainly in the treatment of **depression**. It can also reduce symptoms of **agitation and anxiety**. Background ----------- **Molecular Dynamics (MD) simulation** is the most popular theoretical technique to obtain **macromolecular dynamic information**. **Classical mechanics** is used to represent **atoms as spheres** of a given radius, hardness, charge and mass. The **energy functional** used by **force-fields** is usually composed of two terms: **bonded** and **non-bonded** components: .. math:: E_{pot} = E_{bonded} + E_{non-bonded} where .. math:: E_{bonded} = E_{bond} + E_{angle} + E_{dihedral} and .. math:: E_{non-bonded} = E_{elec} + E_{VdW} .. figure:: MD.png :width: 500pt The combination of the **force-fields** with the **laws of classical mechanics** (Newton’s second law of motion), allows the calculation of the **time evolution** of the system. **Trajectories** of atoms and molecules are determined by numerically solving Newton's equations of motion for a system of interacting particles, where forces between the particles and their potential energies are calculated using the **force-field energy functionals**. **Force-field parameters** for **standard amino-acids** and **nucleic acids** exist and are typically included in **MD packages**. Unfortunately, this is not the case for **small molecules**. That makes a **ligand parameterization** process mandatory if we are interested in simulating a **protein-ligand complex**. How it works ? -------------- This workflow makes extensive use of the **BioExcel Building Blocks library** (`biobb `_). Each step of the process is performed by a **building block** (bb), which are wrappers of tools/scripts that computes a particular functionality (e.g. Solvating a system). If you are interested in expanding/modifying the current workflow, please visit the **existing documentation** for each of the packages `here `_. Most of the steps performed in this pipeline run **GROMACS MD package** tools, one of the most popular MD packages available. Although the **pipeline** is presented **step by step** with associated information, it is extremely advisable to previously spend some time reading documentation about **small molecule parameterization**, to get familiar with the terms used, especially for newcomers to the field. Outcomes / Steps ---------------- This use case will explain: • How to fetch a **ligand structure** in PDB format from the **MMB PDB mirror REST API** • How to **add hydrogen atoms** to the small molecule • How to **energetically minimize** the hydrogen atoms of the molecule • How to generate the **ligand parameters** • How to **find** and **download** the generated **output files** Input ------ - A **ligand code** (3-letter code) - The **ligand net charge** - The **pH**, acidity or alkalinity for the small molecule. **Hydrogen atoms** will be added according to this pH. Outputs ------- - **Interactive and 3D vizualisation** of the **intermediate results** on the small molecule - **Interactive and 3D vizualisation** of the **resulting parameterized structure** - Collection of **parameter files needed to run an MD simulation** including the **small molecule** available to download Targeted audience ----------------- All scientists working in biology related areas where protein study is relevant with a focus on **structural biologists** and **biochemists**. Especially directed to scientists interested in **protein dynamics** and **flexibility**.