BcompB seminar January 13th: Dr David Cole (Immunocore)

BcompB seminar, Monday January 13th, 2-3pm, C42 (Biomedical Sciences Building)


The BcompB seminar in January will be given by Dr David Cole from the company Immunocore. David is a former academic & Welcome Trust Career Development Fellow (at the Cardiff University Institute of Infection & Immunity) and now a group leader at Immunocore, a company that develops T cell receptor mimic therapies (‘biologics’) to target cancer as well as other diseases.

The seminar will include results of soon-to-be-published papers where MD simulation and analysis has contributed significantly to the insights obtained.


Title: In silico development of TCR-based therapies



Soluble bispecific T-cell engagers – next generation cancer immunotherapies:

T cell receptor (TCR)-based therapeutics are currently being developed as the next generation of cancer immunotherapies. A major target for these TCR-based therapies are tumour-associated peptide-human leukocyte antigen complexes (pHLA) because they represent the largest pool of cell surface expressed cancer-specific epitopes.


Engineering a TCR for drug development:

In order to generate a soluble TCR-based drug, we affinity enhance our molecules by over 1-million-fold so that stick to the cancer cell for many hours. We then fuse a T cell stimulator to the other end, effectively turning all of the T cells in a patient’s blood into potential cancer killers. The enhanced affinity of the TCR also ensures potency against even the lowest levels of peptide-human leukocyte antigen complexes (pHLA). These drugs (called ImmTACs) are currently being tested in several clinical trials for a range of diseases.


Computational approaches for uncovering biological mechanisms and developing next generation TCR-based drugs:

Here, the use of structural and computational approaches will be discussed as tools to, 1) better understand the TCR-pHLA interactions, 2) uncover the molecular rules that enable TCRs to be engineered with very strong binding affinities, and 3) develop in silico-based rationale design approaches to generate TCRs with improved specificity and potency for the next generation of TCR-based drugs.

BcompB meeting July 16th

BcompB meeting on simulations methods for allosteric signal propagation

Tuesday July 16th, 2-3pm, C42

Our next BcompB meeting will take place on July 16th, 2-3pm in C42. We will hear about and discuss simulation methods to look into allosteric communication/signal propagation.

Eric Lang and Sofia Oliveira will be speaking about methods that they have developed and applied.

All welcome!

Eric Lang
Calculated pKa Variations Expose Dynamic Allosteric Communication Networks

Allosteric regulation of protein function, the process by which binding of an effector molecule provokes a functional response from a distal site, is critical for metabolic pathways. Yet, the way the allosteric signal is communicated remains elusive, especially in dynamic, entropically driven regulation mechanisms for which no major conformational changes are observed. To identify these dynamic allosteric communication networks, we have developed an approach that monitors the pKa variations of ionizable residues over the course of molecular dynamics simulations performed in the presence and absence of an allosteric regulator. As the pKa of ionizable residues depends on their environment, it represents a simple metric to monitor changes in several complex factors induced by binding an allosteric effector. These factors include Coulombic interactions, hydrogen bonding, and solvation, as well as backbone motions and side chain fluctuations. The predictions that can be made with this method concerning the roles of ionizable residues for allosteric communication can then be easily tested experimentally by changing the working pH of the protein or performing single point mutations.


Sofia Oliveira

Signal propagation in nicotinic receptors: contributions from equilibrium and nonequilibrium simulations

Nicotinic acetylcholine receptors (nAChRs) modulate synaptic transmission in the nervous system. These receptors have emerged as therapeutic targets in drug discovery for treating several conditions, including Alzheimer’s, pain and nicotine addiction. Despite the impressive progress made in the study of this family of receptors, the conformational changes induced by agonist binding/unbinding and how those are communicated to the ion channel remain poorly defined. This is fundamentally important for understanding biological function as well as crucial for rational drug discovery. Here, we have developed a novel computational strategy combing extensive equilibrium and nonequilibrium molecular dynamics simulations to map dynamic and structural changes induced by nicotine in the human α4β2 nAChR. This approach revealed a striking pattern of communication between the binding pockets and the transmembrane domains and allowed for the identification of the sequence of conformational changes associated with the initial steps in this process.

(See Sophia’s recent paper in Structure)

BcompB seminar May 24th: Prof Charles Laughton (Nottingham)

BcompB seminar, Friday May 24th, 2-3pm, C44 (Biomedical Sciences building)

The BcompB seminar in May will be given by Charles (Charlie) Laughton, Professor of Computational Pharmaceutical Science at the University of Nottingham ( https://www.nottingham.ac.uk/pharmacy/people/charles.laughton ).

All welcome!


Enhancing conformational sampling of biomolecules with machine learning and the cloud

Abstract:  I will describe some of our recent research developing new methods for the enhanced sampling of the conformational space of biomolecules, both large and small. I will concentrate on methods that combine molecular dynamics-based sampling with machine learning based supervision in iterative, adaptive, workflows. I will also describe the cloud-based infrastructure and workflow tools we have developed to support this type of research, which we are now making generally available.

BcompB meeting March 19th 2019

BcompB meeting on Molecular Docking

Tuesday March 19th, 2-3pm, C42

During this meeting, we will discuss various aspects molecular docking, including docking small-molecule databases (e.g. to discover lead compounds), protein-protein docking and flexible protein-ligand docking.

With contributions from Richard Sessions, Amaurys Ávila  Ibarra, Debbie Shoemark, Sam Johns and Charlie Colenso, some of the experience in Bristol is highlighted, and indications are given how you can use techniques yourself.

All welcome!


Featured Publication: Unpicking the Cause of Stereoselectivity in Actinorhodin Ketoreductase Variants with Atomistic Simulations

Stefano Artin Serapian and Marc W. van der Kamp

ACS Catalysis
DOI: 10.1021/acscatal.8b04846
Publication Date (Web): January 31, 2019


In this recent ACS Catalysis publication, Stefano Serapian and Marc van der Kamp used a variety of computational tools to shed light on an enticing problem in biocatalysis that has proven very difficult to solve experimentally.

Our enzyme of interest—actinorhodin ketoreductase (actKR)—is found in the soil bacterium Streptomyces coelicolor, where it is normally implicated in the biosynthesis of the antibiotic actinorhodin.  In addition to actKR’s natural scope, as is the case with other ketoreductases, some of its re-engineered variants are highly attractive to synthetic chemists by virtue of their high stereoselectivity in reducing small-molecule achiral ketones to chiral alcohols.

Experimental work on actKR featuring the small model substrate trans-1-decalone (a bicyclic aliphatic ketone) and similarly-sized chiral alcohols suggests that whereas the wild-type enzyme is mildly S-selective, some variants (e.g. the P94L mutant) were entirely S- selective, whereas others (e.g. the V151L mutant) only exhibited R- selectivity.

Featuring classical MD, MM/PBSA and hybrid QM/MM MD with umbrella sampling, our study successfully unravels the causes of such remarkable behaviour in wild-type, P94L, and V151L actKR towards trans-1-decalone.  Explicitly examining both enantiomers of this naturally racemic substrate (something difficult to achieve in vitro), we conclude that changes in stereocontrol across actKR variants can be dictated by a subtle interplay of different causes (including reaction barrier height and accessibility of reactive poses). Interestingly, however, which factor is dominant in conferring stereoselectivity differs per variant.

The protocols we have used were chosen such that they (1) require input of the WT structure only; (2) use relatively limited computational resources (short simulations and semiempirical QM treatment); and (3) can be automated. Our study is thereby a good example of how computational biochemistry can become a practical, useful and efficient tool in biocatalyst engineering, offering perspectives that might otherwise be difficult to explore in vitro.

BcompB seminar Jan 15th: Prof Carmen Domene – Studies of TRP channel activation and modulation using computational approaches

The first BcompB meeting in 2019 will be an external seminar from Prof Carmen Domene (University of Bath).

It will take place on Jan 15th, 2-3pm in LT4 in the School of Chemistry.

Carmen is an expert in the structure, dynamics and mechanism of trans-membrane channels, which her group studies through atomistic molecular dynamics simulations, including enhanced sampling techniques (such as metadynamics).

She will give a talk entitled:

“Studies of TRP channel activation and modulation using computational approaches”


Transient receptor potential (TRP) ion channels constitute a notable family of cation channels involved in the ability of organisms to detect noxious mechanical, thermal and chemical stimuli that gives rise to the perception of pain. One of the most experimentally studied agonist of TRP channels is capsaicin, which is responsible for the burning sensation produced when chili pepper is in contact with organic tissues. Understanding how TRP channels are regulated by capsaicin and other natural products is essential to high impact pharmacological applications, particularly those related to pain treatment. By selected examples from the work we have carried out, I will provide an overview of the current knowledge we have about activation, permeation and selectivity of one of these human molecular thermometers.

PhD opportunities with BcompB

A number of projects with a significant component of computational biochemistry at Bristol University are now open for applications.


GW4 Biomed project to start Sept/Oct 2019 (see eligibility)

Deadline: Nov 23rd 2018 (but contact supervisor first)

Countering antimicrobial resistance: investigating β-lactamase inhibitors using atomistic simulation and experiment.


SWBio DTP projects to start Sept/Oct 2019 (see eligibility)

Deadline: Dec 3rd 2018.

Engineering new polyketide biocatalysts through simulation-led redesign.

Virtual reality interactive molecular modelling for cryoelectron microscopy

Developing better biopharmaceuticals using biomolecular simulation and modelling

Combining theory and experiment to explain the evolution of antibiotic resistance

Constructing catalytically proficient and functionally diverse enzymes from simple, de novo designed proteins

BcompB – Bristol Computational Biochemistry

Due to the many active researchers and research groups that develop and apply methods in computational (molecular) biochemistry at the University of Bristol, we have started BcompB (Bristol Computational Biochemistry). We meet regularly (every 2 months) and discuss topics of general interest or host relevant seminars.

We are building a list of members here.

An overview of Computational Resources (software) created by BcompB members.

You can also find us on twitter: @BcompB

BcompB Committee: