Calculating Water Affinities in Protein Binding Sites with Grand Canonical Monte Carlo and ProtoMS

Aimed at: Anyone interested in predicting whether water molecules in binding sites should be targeted for displacement.

Requirements: Basic knowledge of the Linux command line and basic knowledge of Python.

Abstract: Recent years have witnessed the maturation of our understanding of water in biomolecular association, such that present day structure-based drug design efforts often consider the influence of water on the ligand and protein. A typical concern is whether water molecules within binding sites should be targeted for displacement to improve affinity and specificity. The difficulty of this problem is often compounded by the existence of networks of interdependent waters.

This problem can be directly addressed through our recently developed simulation technique called Grand Canonical Integration (GCI). Simulations in the Grand Canonical ensemble are able to change particle number, providing a direct route to vary the number of waters in buried protein binding sites that circumvent sampling problems in conventional calculations. GCI provides a theoretically rigorous result to translate Grand Canonical simulation data into binding free energies, not just for individual waters but also entire networks.

In this workshop we will present the theoretical basis for GCI and demonstrate its practical application to a protein-ligand system. This workshop employs ProtoMS, the user-friendly Monte Carlo package developed by the Essex group at the University of Southampton.

QM/MM Modelling of Enzyme Reactions

Aimed at: Anyone interested in starting to use QM/MM simulations for their research, in particular for enzyme reactions.

Requirements: Basic knowledge of the Linux command line.

Abstract: The training workshop will introduce non-specialists to the use of combined quantum mechanics/molecular mechanics (QM/MM) methods for modelling enzyme-catalysed reaction mechanisms. Concepts and techniques of QM/MM reaction modelling will be explained through hands-on exercises. During the tutorial, each participant will generate and analyse an energy profile for the reaction catalysed by chorismate mutase.

Introduction to BioSimSpace

Aimed at: Anyone interested in learning how to use the new CCP-BioSim BioSimSpace Python environment for easy setup, running, management and analysis of biomolecular simulations.

Requirements: Knowledge of Python, e.g. as gained from the Python for Biomolecular Modellers workshops. The material from the Python workshops will be online and is self-study, in case you are not able to attend the workshop on Monday.

Abstract: BioSimSpace is the new flagship software being produced in partnership with CCP-BioSim/HEC-BioSim. The software provides an easy-to-use Python environment for manipulating biomolecules, running simulations, and analysing / visualising outputs. BioSimSpace hides the details of using individual simulation and analysis packages behind a common, simple Python interface. This enables you to setup, run and analyse simulations using, e.g. Amber, NAMD or Gromacs, all from the same Python script or Jupyter Python interface.

Visualising Binding Free Energies Using Swap-based Methods

Aimed at: Anyone interested in learning how to run WaterSwap, LigandSwap or ProteinSwap calculations for predicting and visualisaing how changes in a ligand or mutations of a protein affect protein-ligand binding.

Requirements: Knowledge of Python, e.g. as gained from the Python for Biomolecular Modellers workshops. The material from the Python workshops will be online and is self-study, in case you are not able to attend the workshop on Monday.

Abstract: The swap-based methods (WaterSwap, LigandSwap and ProteinSwap) are explicit solvent tools that enable you to calculate absolute and relative protein-ligand binding free energies. They can be used to predict how ligand binding is affected by protein mutations, or to predict selectivity of a ligand to different members of a protein family. In addition, these methods provide an in-built residue-based decomposition of the binding free energy, enabling you to visualise and rationalise predicted changes in binding affinity according to changes in specific protein-ligand interactions. This workshop will introduce the swap-based methods, and will take you through the process of running and analysing WaterSwap, LigandSwap and ProteinSwap simulations.

ISAMBARD: A Python-based API for Biomolecular Structure Analysis and Parametric Design of Protein Structures

Aimed at: Anyone interested in learning how to use the new ISAMBARD Python tools for structural analysis and rational design of proteins and biomolecules.

Requirements: Knowledge of Python, e.g. as gained from the Python for Biomolecular Modellers workshops. The material from the Python workshops will be online and is self-study, in case you are not able to attend the workshop on Monday.

Abstract: In this workshop we introduce ISAMBARD, an open-source Python package for structural analysis and rational design of biomolecules. ISAMBARD provides a generalised approach for modelling any parametrizable protein fold, as well as methods for optimizing and scoring models. In addition, it contains useful tools for the structural analysis of proteins. The practical workshop comprises three parts:

1. An introduction to structure representation in ISAMBARD through the AMPAL (Atom, Monomer, Polymer, Assembly, Ligand) framework. This will provide a basic overview of how to work with biomolecules in ISAMBARD, including selection and analysis of structural elements.

2. Modelling and analysis of coiled-coil structures. This will include parametric analysis of natural coiled coils to extract structural parameters, as well as creating models de novo using ISAMBARD specifications, which can be extended to allow users to create their own parameterisations.
3. Optimization of the structural parameters of models. We will give a brief introduction to meta-heuristics, basic optimization of parametric models and how to analyse and interpret the results.

To get the most out of the workshop, we recommend that you are comfortable with the fundamentals of the Python programming language and the Jupyter Notebook environment.

References:

ISAMBARD: an open-source computational environment for biomolecular analysis, modelling and design. Bioinformatics 2017. doi: 10.1093/bioinformatics/btx352

CCBuilder 2.0: Powerful and accessible coiled-coil modelling, Protein Science 2017. doi: 10.1002/pro.3279