Incorporating MM Polarization in hybrid QM/MM calculations
Lead Research Organisation:
University of Essex
Department Name: Biological Sciences
Abstract
Computer simulation now plays a major role in understanding biological systems and in the design of molecules as new materials and new pharmaceuticals. In cases where it is important to study the molecules in atomic-level detail so that the distribution of electrons within the molecules can be understood, then quantum mechanics is the method of choice. In cases where the environment surrounding these molecules affects this distribution of electrons, then hybrid quantum mechanical / molecular mechanics (QM/MM) methods are used. The QM means that the molecule of interest can be studied accurately; the MM means that the environment that this molecule is in can also be taken into account, albeit at a lower level of accuracy. Within the MM part of these calculations, it is assumed that the electrons have a fixed distribution that does not change in response to the QM region of interest. Here we propose to introduce new computer methods so that the polarization of the electron distribution within the MM region can be taken into account. A simple illustration should highlight the importance of this effect. When a drug binds to an enzyme, the structure of both the drug and the enzyme must flex to accommodate each other. A similar accommodation is occurring in the spatial distribution of the electrons. Ignoring this redistribution (i.e. polarization) is therefore rather like attempting to put on a glove that is almost frozen solid. A significant part of the project will involve work to ensure that these methods can be readily used by other scientists. Applications of this new method will enable increased atomic and molecular level understanding of biological processes. The scientists that will benefit will not only include theoreticians but also enzymologists, those involved in drug design, bioinorganic chemists, photochemists, material scientists, plant scientists, spectroscopists, and those involved in biotechnology software companies.
Technical Summary
Hybrid quantum mechanical / molecular mechanics (QM/MM) methods have now developed into powerful research tools for analysing mechanisms of both inorganic processes and enzymes. Because of the underlying quantum mechanical (QM) treatment of the region of interest, they provide the main approach to studying bond rearrangements in proteins. Advances in quantum chemistry mean that these calculations can now be carried out with reasonable accuracy. The molecular mechanics (MM) treatment of the environment ensures realistic calculations. Usually in QM/MM, the QM entity is polarized by the MM entity but the MM entity is not polarized. This asymmetry is vaguely acceptable because the focus is on the QM region. Nevertheless, there is evidence to suggest that MM polarization can be important and so here we propose to implement MM polarization into QM/MM. Here we propose to do this using induced charges, for several reasons. Firstly, they are easy to implement (so any advantages gained can be implemented in additional computer codes), secondly they are based on the electrostatic potential and so are fully consistent with the derivation of many modern force fields. Thirdly, the polarization energy determined is readily compatible with that arising from polarization of the wave function. Fourthly, the computational cost of MM polarization via induced charges is low. Optimal strategies for the efficient use of the methods will be determined. A significant part of the project will involve work to ensure that these methods can be readily used by other scientists. Applications of this new method will enable increased atomic and molecular level understanding of biological processes such as characterisation of transition states and calculation of kinetic isotope effects, understanding transition state stabilization, biological electron transfer, protein-ligand interactions, design of anti-cancer drugs and sequence specific DNA binding ligands.
Organisations
- University of Essex (Lead Research Organisation)
- UNIVERSITY OF NOTTINGHAM (Collaboration)
- ASTON UNIVERSITY (Collaboration)
- University of South Bohemia (Collaboration)
- UNIVERSITY OF READING (Collaboration)
- University of Warwick (Collaboration)
- University of Pecs (Collaboration)
- GlaxoSmithKline (GSK) (Collaboration)
- OnTarget Chemistry (Collaboration)
- UNIVERSITY OF CAMBRIDGE (Collaboration)
- Pharmnovo AB/Pharmnovo UK Ltd (Collaboration)
- KING'S COLLEGE LONDON (Collaboration)
Publications
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Wootten D
(2016)
The Extracellular Surface of the GLP-1 Receptor Is a Molecular Trigger for Biased Agonism.
in Cell
Description | The search for a new drug may start on the computer by 'docking' potential molecules into a structure of the drug target, which is typically an enzyme or a receptor. Molecules that are calculated to fit well can therefore be made and tested experimentally, while those calculated to have a poor fit can be ignored, thus saving time and expense. However, these calculations do not always work well. These calculations usually assumes that the atomic charge distribution on the molecule and the enzyme does not change when the molecule approaches the enzyme even when the charges on some of the atoms are quite high and might therefore affect each other, i.e. one molecule might polarize the other. We have developed a method of including enzyme polarization and ligand polarization in docking that can be combined with standard state-of-the art docking software. This should greatly reduce one of the main errors in docking. Inclusion of polarization by this method typically halves the proportion of compounds incorrectly docked using GLIDE, a state-of the art docking program and therefore has the potential to facilitate the drug design process. |
Exploitation Route | It has since been proposed that water molecules play a far bigger role in drug design than was previously envisaged, as a drug will benefit energetically from displacing an 'unhappy' water molecule (i.e. one that binds weakly to the protein), but will not benefit from displacing a 'happy' water molecule. Jon Mason, Heptares, is one of the main proponents (as judged by frequency of conference talks) of the importance of this effect in drug design. Certainly, we observe greater improvement from our methods when appropriate water molecules are included, but the key question is which water molecules to include. The natural extension to our work is to investigate the energetics of water placement within protein active sites by including polarization, so that more accurate inclusion of 'happy' water molecules can be used to give improved docking results. At one level this is trivial, but we have opened discussions with Dr Mason (and also with Schrodinger who produce relevant software) to test these ideas on public domain structures that are nevertheless pharmaceutically important and where the subtleties of ligand binding are well-understood. Collaboration with Schrodinger or pharma is likely to ensure that the methods are well-focused to have the maximum impact. |
Sectors | Agriculture, Food and Drink,Chemicals,Digital/Communication/Information Technologies (including Software),Pharmaceuticals and Medical Biotechnology |
URL | http://ftp://ftp.essex.ac.uk/pub/oyster |
Description | Industry interchange programme |
Amount | £50,210 (GBP) |
Organisation | Biotechnology and Biological Sciences Research Council (BBSRC) |
Sector | Public |
Country | United Kingdom |
Start | 10/2010 |
End | 06/2011 |
Description | Project Grant |
Amount | £175,421 (GBP) |
Funding ID | PG/12/59/29795 |
Organisation | British Heart Foundation (BHF) |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 03/2014 |
End | 02/2017 |
Description | Research Leader Fellowship / Industry Interchange |
Amount | £98,509 (GBP) |
Funding ID | G1001812 |
Organisation | Medical Research Council (MRC) |
Sector | Public |
Country | United Kingdom |
Start | 10/2011 |
End | 09/2014 |
Description | CGRP antagonists |
Organisation | Aston University |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Modelling interactions of ligands with the CGRP receptor and other proteins. |
Collaborator Contribution | Pharmonovo supply ligands and coordinate the project David Kendall, PhD, Professor of Pharmacology, University of Nottingham; in vitro investigations of receptor activity and behavioural evaluation of novel compounds in animal models. Over 30 years of experience of GPCR pharmacology. OnTarget Chemistry. Fredrik Lehmann: synthetic chemistry University of Reading. Graeme Cottrell, PhD, Lecturer in Cellular and Molecular Neuroscience; In vitro investigations of the effects of novel compounds on CGRP trafficking and signalling; Over 10 year experience in GPCR trafficking and signalling University of Aston. David Poyner, PhD, Professor of Pharmacology. Mapping antagonist binding sites on the CGRP receptor. 25 year experience of studying the CGRP receptor. University of Essex, Mike Hough, X-ray crystallography Kings College, London. Susan Brain, PhD, Professor of Pharmacology, Vascular Biology and Inflammation. In vivo measurements of blood flow in murine models, especially in first pre-clinical experiments to determine potency, mode of administration and duration of action. PharmInVivo. Zsuzsanna Helyes, MD, PhD, DSc. PharmInVivo is a spin-out based in the Department of Pharmacology and Pharmacotherapy at the Medical Faculty & Szentagothai Research Center of the University of Pécs. She has worked in the fields of pain and inflammation for decades and has great expertise in a variety of experimental models with special emphasis on in vivo studies. |
Impact | This is a new multi-disciplinary collaboration that has submitted a grant application to the Wellcome Trust, which was not funded. Discussions within this consortium helped Poyner and Reynolds to submit a successful grant on CGRP. |
Start Year | 2013 |
Description | CGRP antagonists |
Organisation | King's College London |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Modelling interactions of ligands with the CGRP receptor and other proteins. |
Collaborator Contribution | Pharmonovo supply ligands and coordinate the project David Kendall, PhD, Professor of Pharmacology, University of Nottingham; in vitro investigations of receptor activity and behavioural evaluation of novel compounds in animal models. Over 30 years of experience of GPCR pharmacology. OnTarget Chemistry. Fredrik Lehmann: synthetic chemistry University of Reading. Graeme Cottrell, PhD, Lecturer in Cellular and Molecular Neuroscience; In vitro investigations of the effects of novel compounds on CGRP trafficking and signalling; Over 10 year experience in GPCR trafficking and signalling University of Aston. David Poyner, PhD, Professor of Pharmacology. Mapping antagonist binding sites on the CGRP receptor. 25 year experience of studying the CGRP receptor. University of Essex, Mike Hough, X-ray crystallography Kings College, London. Susan Brain, PhD, Professor of Pharmacology, Vascular Biology and Inflammation. In vivo measurements of blood flow in murine models, especially in first pre-clinical experiments to determine potency, mode of administration and duration of action. PharmInVivo. Zsuzsanna Helyes, MD, PhD, DSc. PharmInVivo is a spin-out based in the Department of Pharmacology and Pharmacotherapy at the Medical Faculty & Szentagothai Research Center of the University of Pécs. She has worked in the fields of pain and inflammation for decades and has great expertise in a variety of experimental models with special emphasis on in vivo studies. |
Impact | This is a new multi-disciplinary collaboration that has submitted a grant application to the Wellcome Trust, which was not funded. Discussions within this consortium helped Poyner and Reynolds to submit a successful grant on CGRP. |
Start Year | 2013 |
Description | CGRP antagonists |
Organisation | OnTarget Chemistry |
Country | Sweden |
Sector | Academic/University |
PI Contribution | Modelling interactions of ligands with the CGRP receptor and other proteins. |
Collaborator Contribution | Pharmonovo supply ligands and coordinate the project David Kendall, PhD, Professor of Pharmacology, University of Nottingham; in vitro investigations of receptor activity and behavioural evaluation of novel compounds in animal models. Over 30 years of experience of GPCR pharmacology. OnTarget Chemistry. Fredrik Lehmann: synthetic chemistry University of Reading. Graeme Cottrell, PhD, Lecturer in Cellular and Molecular Neuroscience; In vitro investigations of the effects of novel compounds on CGRP trafficking and signalling; Over 10 year experience in GPCR trafficking and signalling University of Aston. David Poyner, PhD, Professor of Pharmacology. Mapping antagonist binding sites on the CGRP receptor. 25 year experience of studying the CGRP receptor. University of Essex, Mike Hough, X-ray crystallography Kings College, London. Susan Brain, PhD, Professor of Pharmacology, Vascular Biology and Inflammation. In vivo measurements of blood flow in murine models, especially in first pre-clinical experiments to determine potency, mode of administration and duration of action. PharmInVivo. Zsuzsanna Helyes, MD, PhD, DSc. PharmInVivo is a spin-out based in the Department of Pharmacology and Pharmacotherapy at the Medical Faculty & Szentagothai Research Center of the University of Pécs. She has worked in the fields of pain and inflammation for decades and has great expertise in a variety of experimental models with special emphasis on in vivo studies. |
Impact | This is a new multi-disciplinary collaboration that has submitted a grant application to the Wellcome Trust, which was not funded. Discussions within this consortium helped Poyner and Reynolds to submit a successful grant on CGRP. |
Start Year | 2013 |
Description | CGRP antagonists |
Organisation | Pharmnovo AB/Pharmnovo UK Ltd |
Country | Sweden |
Sector | Private |
PI Contribution | Modelling interactions of ligands with the CGRP receptor and other proteins. |
Collaborator Contribution | Pharmonovo supply ligands and coordinate the project David Kendall, PhD, Professor of Pharmacology, University of Nottingham; in vitro investigations of receptor activity and behavioural evaluation of novel compounds in animal models. Over 30 years of experience of GPCR pharmacology. OnTarget Chemistry. Fredrik Lehmann: synthetic chemistry University of Reading. Graeme Cottrell, PhD, Lecturer in Cellular and Molecular Neuroscience; In vitro investigations of the effects of novel compounds on CGRP trafficking and signalling; Over 10 year experience in GPCR trafficking and signalling University of Aston. David Poyner, PhD, Professor of Pharmacology. Mapping antagonist binding sites on the CGRP receptor. 25 year experience of studying the CGRP receptor. University of Essex, Mike Hough, X-ray crystallography Kings College, London. Susan Brain, PhD, Professor of Pharmacology, Vascular Biology and Inflammation. In vivo measurements of blood flow in murine models, especially in first pre-clinical experiments to determine potency, mode of administration and duration of action. PharmInVivo. Zsuzsanna Helyes, MD, PhD, DSc. PharmInVivo is a spin-out based in the Department of Pharmacology and Pharmacotherapy at the Medical Faculty & Szentagothai Research Center of the University of Pécs. She has worked in the fields of pain and inflammation for decades and has great expertise in a variety of experimental models with special emphasis on in vivo studies. |
Impact | This is a new multi-disciplinary collaboration that has submitted a grant application to the Wellcome Trust, which was not funded. Discussions within this consortium helped Poyner and Reynolds to submit a successful grant on CGRP. |
Start Year | 2013 |
Description | CGRP antagonists |
Organisation | University of Nottingham |
Department | School of Biomedical Sciences Nottingham |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Modelling interactions of ligands with the CGRP receptor and other proteins. |
Collaborator Contribution | Pharmonovo supply ligands and coordinate the project David Kendall, PhD, Professor of Pharmacology, University of Nottingham; in vitro investigations of receptor activity and behavioural evaluation of novel compounds in animal models. Over 30 years of experience of GPCR pharmacology. OnTarget Chemistry. Fredrik Lehmann: synthetic chemistry University of Reading. Graeme Cottrell, PhD, Lecturer in Cellular and Molecular Neuroscience; In vitro investigations of the effects of novel compounds on CGRP trafficking and signalling; Over 10 year experience in GPCR trafficking and signalling University of Aston. David Poyner, PhD, Professor of Pharmacology. Mapping antagonist binding sites on the CGRP receptor. 25 year experience of studying the CGRP receptor. University of Essex, Mike Hough, X-ray crystallography Kings College, London. Susan Brain, PhD, Professor of Pharmacology, Vascular Biology and Inflammation. In vivo measurements of blood flow in murine models, especially in first pre-clinical experiments to determine potency, mode of administration and duration of action. PharmInVivo. Zsuzsanna Helyes, MD, PhD, DSc. PharmInVivo is a spin-out based in the Department of Pharmacology and Pharmacotherapy at the Medical Faculty & Szentagothai Research Center of the University of Pécs. She has worked in the fields of pain and inflammation for decades and has great expertise in a variety of experimental models with special emphasis on in vivo studies. |
Impact | This is a new multi-disciplinary collaboration that has submitted a grant application to the Wellcome Trust, which was not funded. Discussions within this consortium helped Poyner and Reynolds to submit a successful grant on CGRP. |
Start Year | 2013 |
Description | CGRP antagonists |
Organisation | University of Pecs |
Department | Department of Pharmacology and Pharmacotherapy |
Country | Hungary |
Sector | Academic/University |
PI Contribution | Modelling interactions of ligands with the CGRP receptor and other proteins. |
Collaborator Contribution | Pharmonovo supply ligands and coordinate the project David Kendall, PhD, Professor of Pharmacology, University of Nottingham; in vitro investigations of receptor activity and behavioural evaluation of novel compounds in animal models. Over 30 years of experience of GPCR pharmacology. OnTarget Chemistry. Fredrik Lehmann: synthetic chemistry University of Reading. Graeme Cottrell, PhD, Lecturer in Cellular and Molecular Neuroscience; In vitro investigations of the effects of novel compounds on CGRP trafficking and signalling; Over 10 year experience in GPCR trafficking and signalling University of Aston. David Poyner, PhD, Professor of Pharmacology. Mapping antagonist binding sites on the CGRP receptor. 25 year experience of studying the CGRP receptor. University of Essex, Mike Hough, X-ray crystallography Kings College, London. Susan Brain, PhD, Professor of Pharmacology, Vascular Biology and Inflammation. In vivo measurements of blood flow in murine models, especially in first pre-clinical experiments to determine potency, mode of administration and duration of action. PharmInVivo. Zsuzsanna Helyes, MD, PhD, DSc. PharmInVivo is a spin-out based in the Department of Pharmacology and Pharmacotherapy at the Medical Faculty & Szentagothai Research Center of the University of Pécs. She has worked in the fields of pain and inflammation for decades and has great expertise in a variety of experimental models with special emphasis on in vivo studies. |
Impact | This is a new multi-disciplinary collaboration that has submitted a grant application to the Wellcome Trust, which was not funded. Discussions within this consortium helped Poyner and Reynolds to submit a successful grant on CGRP. |
Start Year | 2013 |
Description | CGRP antagonists |
Organisation | University of Reading |
Department | School of Pharmacy Reading |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Modelling interactions of ligands with the CGRP receptor and other proteins. |
Collaborator Contribution | Pharmonovo supply ligands and coordinate the project David Kendall, PhD, Professor of Pharmacology, University of Nottingham; in vitro investigations of receptor activity and behavioural evaluation of novel compounds in animal models. Over 30 years of experience of GPCR pharmacology. OnTarget Chemistry. Fredrik Lehmann: synthetic chemistry University of Reading. Graeme Cottrell, PhD, Lecturer in Cellular and Molecular Neuroscience; In vitro investigations of the effects of novel compounds on CGRP trafficking and signalling; Over 10 year experience in GPCR trafficking and signalling University of Aston. David Poyner, PhD, Professor of Pharmacology. Mapping antagonist binding sites on the CGRP receptor. 25 year experience of studying the CGRP receptor. University of Essex, Mike Hough, X-ray crystallography Kings College, London. Susan Brain, PhD, Professor of Pharmacology, Vascular Biology and Inflammation. In vivo measurements of blood flow in murine models, especially in first pre-clinical experiments to determine potency, mode of administration and duration of action. PharmInVivo. Zsuzsanna Helyes, MD, PhD, DSc. PharmInVivo is a spin-out based in the Department of Pharmacology and Pharmacotherapy at the Medical Faculty & Szentagothai Research Center of the University of Pécs. She has worked in the fields of pain and inflammation for decades and has great expertise in a variety of experimental models with special emphasis on in vivo studies. |
Impact | This is a new multi-disciplinary collaboration that has submitted a grant application to the Wellcome Trust, which was not funded. Discussions within this consortium helped Poyner and Reynolds to submit a successful grant on CGRP. |
Start Year | 2013 |
Description | Glucagon and GLP-1 receptor |
Organisation | Aston University |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Molecular modelling: interactions between peptide ligand and receptor |
Collaborator Contribution | Yeast Cell Biology (Ladds, Warwick until mid 2015; now Cambridge); Pharmacology (Poyner, Aston) |
Impact | multi-disciplinary: (i) cell biology (Warwick), (ii) pharmacology (Aston), (iii) computational chemistry (comparative modelling, docking, Essex) Publication in preparation, entitled 'Modulation of glucagon receptor pharmacology by RAMP2', by Weston, C., Lu, J., Richards, G. O., Roberts, D. J., Skerry, T. M., Dowell, S. J., Willars, G. B., Reynolds C.A. and Ladds, G. Grant Application on biased signalling in the GLP-1 receptor in preparation (with G. Ladds, D.R. Poyner). |
Start Year | 2014 |
Description | Glucagon and GLP-1 receptor |
Organisation | University of Cambridge |
Department | Department of Pharmacology |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Molecular modelling: interactions between peptide ligand and receptor |
Collaborator Contribution | Yeast Cell Biology (Ladds, Warwick until mid 2015; now Cambridge); Pharmacology (Poyner, Aston) |
Impact | multi-disciplinary: (i) cell biology (Warwick), (ii) pharmacology (Aston), (iii) computational chemistry (comparative modelling, docking, Essex) Publication in preparation, entitled 'Modulation of glucagon receptor pharmacology by RAMP2', by Weston, C., Lu, J., Richards, G. O., Roberts, D. J., Skerry, T. M., Dowell, S. J., Willars, G. B., Reynolds C.A. and Ladds, G. Grant Application on biased signalling in the GLP-1 receptor in preparation (with G. Ladds, D.R. Poyner). |
Start Year | 2014 |
Description | Glucagon and GLP-1 receptor |
Organisation | University of Warwick |
Department | Warwick Medical School |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Molecular modelling: interactions between peptide ligand and receptor |
Collaborator Contribution | Yeast Cell Biology (Ladds, Warwick until mid 2015; now Cambridge); Pharmacology (Poyner, Aston) |
Impact | multi-disciplinary: (i) cell biology (Warwick), (ii) pharmacology (Aston), (iii) computational chemistry (comparative modelling, docking, Essex) Publication in preparation, entitled 'Modulation of glucagon receptor pharmacology by RAMP2', by Weston, C., Lu, J., Richards, G. O., Roberts, D. J., Skerry, T. M., Dowell, S. J., Willars, G. B., Reynolds C.A. and Ladds, G. Grant Application on biased signalling in the GLP-1 receptor in preparation (with G. Ladds, D.R. Poyner). |
Start Year | 2014 |
Description | Industry Interchange |
Organisation | GlaxoSmithKline (GSK) |
Department | Discovery Partnerships with Academia |
Country | Global |
Sector | Private |
PI Contribution | Novel QM/MM methods that include a polarizable MM region for application to fragment-based drug design (FBDD) |
Collaborator Contribution | Advice in how to apply these methods to FBDD |
Impact | See publications involving Ian Wall |
Start Year | 2010 |
Description | Modelling polarization |
Organisation | University of South Bohemia |
Country | Czech Republic |
Sector | Academic/University |
PI Contribution | Intellectual input, computing resources and programming skills |
Collaborator Contribution | Intellectual input, computing resources and programming skills, with an emphasis on quantum chemistry and programing. |
Impact | Polarized docking software |
Start Year | 2011 |
Title | polarization software |
Description | The search for a new drug may start on the computer by 'docking' potential molecules into a structure of the drug target, which is typically an enzyme or a receptor. Molecules that are calculated to fit well can therefore be made and tested experimentally, while those calculated to have a poor fit can be ignored, thus saving time and expense. However, these calculations do not always work well. These calculations usually assumes that the atomic charge distribution on the molecule and the enzyme does not change when the molecule approaches the enzyme even when the charges on some of the atoms are quite high and might therefore affect each other, i.e. one molecule might polarize the other. We have developed a method of including enzyme polarization and ligand polarization in docking that can be combined with standard state-of-the art docking software, e.g. Glide. This should greatly reduce one of the main errors in docking. The method is based on a series of Perl scripts and converts an induced dipole to a set of induced charges. The induced dipole can be calculated classically, or quantum mechanically. Typically the induced dpole at the enzyme is calculated from the ligand quantum mechanical electrostatic potential at the atoms of the enzyme. |
Type Of Technology | Software |
Year Produced | 2011 |
Open Source License? | Yes |
Impact | Inclusion of polarization by this method typically halves the proportion of compounds incorrectly docked using GLIDE, a state-of the art docking program and therefore has the potential to facilitate the drug design process. This is particularly true when appropriate water molecules are included as part of the enzyme target. |
URL | http://ftp://ftp.essex.ac.uk/pub/oyster/polarization |
Description | Drug Design Workshop for the giften and able |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Schools |
Results and Impact | 8 Gifted and able students from Bromfords School, Essex, attended a week-long drug design workshop, which greatly increased the pupils enthusiasm for science. |
Year(s) Of Engagement Activity | 2016 |