Difference between revisions of "BIN-SX-Molecular forcefields"

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<div style="padding:5px; border:1px solid #000000; background-color:#b3dbce; font-size:300%; font-weight:400; color: #000000; width:100%;">
 
Molecular Forcefields
 
Molecular Forcefields
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(Principles and components - molecular mechanics, and statistical pseudo-energies.)
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<b>Keywords:</b>&nbsp;
 
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Principles and components - molecular mechanics, and statistical pseudo-energies.
 
 
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<div style="font-size:118%;">
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== Abstract ==
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<b>Abstract:</b><br />
 
<section begin=abstract />
 
<section begin=abstract />
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<!-- included from "../components/BIN-SX-Molecular_forcefields.components.wtxt", section: "abstract" -->
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A brief introduction to molecular forcefields.
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...
 
 
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== This unit ... ==
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=== Prerequisites ===
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<td style="padding:10px;">
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<!-- included from "../components/BIN-SX-Molecular_forcefields.components.wtxt", section: "prerequisites" -->
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<b>Objectives:</b><br />
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<!-- included from "ABC-unit_components.wtxt", section: "notes-external_prerequisites" -->
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This unit will ...
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You need the following preparation before beginning this unit. If you are not familiar with this material from courses you took previously, you need to prepare yourself from other information sources:
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* ... briefly introduce molecular mechanics and statistical forcefields.
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<td style="padding:10px;">
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<b>Outcomes:</b><br />
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After working through this unit you ...
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* ... are familar with the components of a molecular mechanics forcefield, and how statistical forcefields are constructed.
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<b>Deliverables:</b><br />
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<li><b>Time management</b>: Before you begin, estimate how long it will take you to complete this unit. Then, record in your course journal: the number of hours you estimated, the number of hours you worked on the unit, and the amount of time that passed between start and completion of this unit.</li>
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<li><b>Journal</b>: Document your progress in your [[FND-Journal|Course Journal]]. Some tasks may ask you to include specific items in your journal. Don't overlook these.</li>
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<li><b>Insights</b>: If you find something particularly noteworthy about this unit, make a note in your [[ABC-Insights|'''insights!''' page]].</li>
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<section end=deliverables />
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<hr>
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<section begin=prerequisites />
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<b>Prerequisites:</b><br />
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You need the following preparation before beginning this unit. If you are not familiar with this material from courses you took previously, you need to prepare yourself from other information sources:<br />
 
*<b>Properties of atoms</b>: the periodic system, covalent and non-covalent interactions; naming atoms and molecules;
 
*<b>Properties of atoms</b>: the periodic system, covalent and non-covalent interactions; naming atoms and molecules;
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<!-- included from "FND-prerequisites.wtxt", section: "molecules" -->
 
 
*<b>Properties of molecules</b>: molecular structure, the hydrophobic effect; stereochemistry; steric complementarity as the foundation of molecular function.
 
*<b>Properties of molecules</b>: molecular structure, the hydrophobic effect; stereochemistry; steric complementarity as the foundation of molecular function.
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<!-- included from "FND-prerequisites.wtxt", section: "physchem" -->
 
 
*<b>Physical chemistry</b>: Kinetics and equilibria, transition states, chemical reactions; enthalpy, entropy and free energy; acid-base equilibria, Boltzmann's law.
 
*<b>Physical chemistry</b>: Kinetics and equilibria, transition states, chemical reactions; enthalpy, entropy and free energy; acid-base equilibria, Boltzmann's law.
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<!-- included from "ABC-unit_components.wtxt", section: "notes-prerequisites" -->
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This unit builds on material covered in the following prerequisite units:<br />
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You need to complete the following units before beginning this one:
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*[[BIN-SX-Chimera|BIN-SX-Chimera (UCSF ChimeraX: Structure Visualization and Analysis)]]
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*[[BIN-SX-Chimera]]
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<section end=prerequisites />
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*[[FND-STA-Information_theory]]
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=== Objectives ===
 
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=== Outcomes ===
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__TOC__
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=== Deliverables ===
 
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*<b>Time management</b>: Before you begin, estimate how long it will take you to complete this unit. Then, record in your course journal: the number of hours you estimated, the number of hours you worked on the unit, and the amount of time that passed between start and completion of this unit.
 
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<!-- included from "ABC-unit_components.wtxt", section: "deliverables-journal" -->
 
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*<b>Journal</b>: Document your progress in your [[FND-Journal|Course Journal]]. Some tasks may ask you to include specific items in your journal. Don't overlook these.
 
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*<b>Insights</b>: If you find something particularly noteworthy about this unit, make a note in your [[ABC-Insights|'''insights!''' page]].
 
  
 
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=== Evaluation ===
 
=== Evaluation ===
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<b>Evaluation: NA</b><br />
 
<b>Evaluation: NA</b><br />
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:This unit is not evaluated for course marks.
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<div style="margin-left: 2rem;">This unit is not evaluated for course marks.</div>
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== Contents ==
 
== Contents ==
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{{Task|1=
 
{{Task|1=
 
*Read the introductory notes on {{ABC-PDF|BIN-SX-Molecular_forcefields|forcefields for macromolecular structure analysis}}.
 
*Read the introductory notes on {{ABC-PDF|BIN-SX-Molecular_forcefields|forcefields for macromolecular structure analysis}}.
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==A Point Mutation==
 
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To illustrate how homology modelling works in principle, let's consider changing the sequence of a single amino acid, based on a structural template.
 
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Such minimal changes to structure models can be done directly in Chimera. Let us consider the residue <code>A&nbsp;42</code> of the 1BM8 structure. It is oriented towards the core of the protein, but most other Mbp1 orthologs have a larger amino acid in this position, <code>V</code>, or even <code>I</code>.
 
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{{task|1=
 
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# Open <code>1BM8</code> in Chimera, hide the ribbons and show all atoms as a stick model.
 
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# Color the protein white.
 
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# Open the sequence window and select <code>A&nbsp;42</code>. Color it red. Choose '''Actions&nbsp;&rarr;&nbsp;Set pivot'''. Then study how nicely the alanine sidechain fits into the cavity formed by its surrounding residues.
 
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# To emphasize this better, hide the solvent molecules and select only the protein atoms. Display them as a '''sphere''' model to better appreciate the packing, i.e. the Van der Waals contacts we discussed in class. Use the '''Favorites&nbsp;&rarr;&nbsp;Side view''' panel to move the clipping plane and see a section through the protein. Study the packing, in particular, note that the additional methyl groups of a valine or isoleucine would not have enough space in the structure. Then restore the clipping planes so you can see the whole molecule.
 
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# Lets simplify the view: choose '''Actions &rarr; Atoms/Bonds &rarr; backbone&nbsp;only &rarr; chain&nbsp;trace'''. Then select <code>A&nbsp;42</code> again in the sequence window and choose '''Actions &rarr; Atoms/Bonds &rarr; show'''.
 
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# Add the surrounding residues: choose '''Select &rarr; Zone...'''. In the window, see that the box is checked that selects all atoms at a distance of less then 5&Aring; to the current selection, and check the lower box to select the whole residue of any atom that matches the distance cutoff criterion. Click '''OK''' and choose '''Actions &rarr; Atoms/Bonds &rarr; show'''.
 
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#Select <code>A&nbsp;42</code> again: '''left-click''' (control click) on any atom of the alanine to select the atom, then '''up-arrow''' to select the entire residue. Now let's mutate this residue to isoleucine.
 
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#Choose '''Tools &rarr; Structure&nbsp;Editing &rarr; Rotamers''' and select <code>ILE</code> as the rotamer type. Click '''OK''', a window will pop up that shows you the possible rotamers for isoleucine together with their database-derived probabilities; you can select them in the window and cycle through them with your arrow keys. But note that the probabilities are '''very''' different - and thus show you high-energy and low-energy rotamers to choose from. Therefore, unless you have compelling reasons to do otherwise, try to find the highest-probability rotamer that may fit. This is where your stereo viewing practice becomes important, if not essential. It is really, really hard to do this reasonably in a 2D image! It becomes quite obvious in 3D. Btw: I find such "quantitative" work - where the real distances are important - easier in '''orthographic''' than in '''perspective''' view (cf. the '''Camera''' panel).
 
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#I find that the first rotamer is actually not such a bad fit. The <code>CD</code> atom comes close to the sidechains of <code>I&nbsp;25</code> and <code>L&nbsp;96</code>. But we can assume that these are somewhat mobile and can accommodate a denser packing, because - as you can easily verify in your Jalview alignment - it is '''NOT''' the case that sequences that have <code>I&nbsp;42</code>, have a smaller residue in position <code>25</code> and/or <code>96</code>. So let's accept the most frequent <code>ILE</code> rotamer by selecting it in the rotamer window and clicking '''OK''' (while '''existing side chain(s): replace''' is selected).
 
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#Done.
 
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}}
 
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If you want to go over this in more detail, check the video tutorial on YouTube published by the NIAID bioinformatics group [http://www.youtube.com/watch?v=bcXMexN6hjY '''here''']. I would also encourage you to go over [http://www.youtube.com/watch?v=eJkrvr-xeXY '''Part 2 of the video tutorial'''] that discusses how to check for and resolve (by energy minimization) steric clashes. But do remember that it is not clear whether energy minimization will make your structure more correct in the sense of a smaller overall RMSD with the real, mutated protein.
 
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What we have done here with one residue is exactly the way homology modeling works with entire sequences. The homology modelling program simply changes '''all''' amino acids to the residues of the '''target sequence''', based on the '''template structure'''. Let's now build a homology model for YFO Mbp1.
 
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== Further reading, links and resources ==
 
== Further reading, links and resources ==
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{{#pmid: 32950937}}
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<div class="reference-box">[http://www.ks.uiuc.edu/Training/Workshop/SanFrancisco/lectures/Wednesday-ForceFields.pdf '''Force Fields for MD simulations'''] a concise but comprehensive slide-deck from the [http://www.ks.uiuc.edu/Training/Workshop/SanFrancisco/ UIUC Computational Biophysics Workshop, San Francisco 2005]. (Author probably Emad Tajkhorshid)</div>
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<!-- <div class="reference-box">[http://www.ncbi.nlm.nih.gov]</div> -->
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{{#pmid: 18446282}}
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<b>If in doubt, ask!</b> If anything about this learning unit is not clear to you, do not proceed blindly but ask for clarification. Post your question on the course mailing list: others are likely to have similar problems. Or send an email to your instructor.
 
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Latest revision as of 11:44, 28 September 2020

Molecular Forcefields

(Principles and components - molecular mechanics, and statistical pseudo-energies.)


 


Abstract:

A brief introduction to molecular forcefields.

Objectives:
This unit will ...

  • ... briefly introduce molecular mechanics and statistical forcefields.

Outcomes:
After working through this unit you ...

  • ... are familar with the components of a molecular mechanics forcefield, and how statistical forcefields are constructed.

Deliverables:

  • Time management: Before you begin, estimate how long it will take you to complete this unit. Then, record in your course journal: the number of hours you estimated, the number of hours you worked on the unit, and the amount of time that passed between start and completion of this unit.
  • Journal: Document your progress in your Course Journal. Some tasks may ask you to include specific items in your journal. Don't overlook these.
  • Insights: If you find something particularly noteworthy about this unit, make a note in your insights! page.

    • Prerequisites:
    You need the following preparation before beginning this unit. If you are not familiar with this material from courses you took previously, you need to prepare yourself from other information sources:

    • Properties of atoms: the periodic system, covalent and non-covalent interactions; naming atoms and molecules;
    • Properties of molecules: molecular structure, the hydrophobic effect; stereochemistry; steric complementarity as the foundation of molecular function.
    • Physical chemistry: Kinetics and equilibria, transition states, chemical reactions; enthalpy, entropy and free energy; acid-base equilibria, Boltzmann's law.

    This unit builds on material covered in the following prerequisite units:


     



     



     


    Evaluation

    Evaluation: NA

    This unit is not evaluated for course marks.

    Contents

    Task:


     

    Further reading, links and resources

    Salsbury & Lemkul (2020) Recent developments in empirical atomistic force fields for nucleic acids and applications to studies of folding and dynamics. Curr Opin Struct Biol 67:9-17. (pmid: 32950937)

    [ PubMed ] [ DOI ] Nucleic acids play critical roles in carrying genetic information, participating in catalysis, and preserving chromosomal structure. Despite over a century of study, efforts to understand the dynamics and structure-function relationships of DNA and RNA at the atomic level are still ongoing. Molecular dynamics (MD) simulations augment experiments by providing atomistic resolution and quantitative relationships between structure and conformational energy. Steady advancements in computer hardware, software, and atomistic force fields (FFs) over 40 years have facilitated new discoveries. Here, we review nucleic acid FF development with emphasis on recent refinements that have improved descriptions of important nucleic acid properties. We then discuss several key examples of successes and challenges in modeling nucleic acid structure and dynamics using the latest FFs.

    Force Fields for MD simulations a concise but comprehensive slide-deck from the UIUC Computational Biophysics Workshop, San Francisco 2005. (Author probably Emad Tajkhorshid)
    Guvench & MacKerell (2008) Comparison of protein force fields for molecular dynamics simulations. Methods Mol Biol 443:63-88. (pmid: 18446282)

    [ PubMed ] [ DOI ] In the context of molecular dynamics simulations of proteins, the term "force field" refers to the combination of a mathematical formula and associated parameters that are used to describe the energy of the protein as a function of its atomic coordinates. In this review, we describe the functional forms and parameterization protocols of the widely used biomolecular force fields Amber, CHARMM, GROMOS, and OPLS-AA. We also summarize the ability of various readily available noncommercial molecular dynamics packages to perform simulations using these force fields, as well as to use modern methods for the generation of constant-temperature, constant-pressure ensembles and to treat long-range interactions. Finally, we finish with a discussion of the ability of these force fields to support the modeling of proteins in conjunction with nucleic acids, lipids, carbohydrates, and/or small molecules.

    Notes


     


    About ...
     
    Author:

    Boris Steipe <boris.steipe@utoronto.ca>

    Created:

    2017-08-05

    Modified:

    2020-09-26

    Version:

    1.1

    Version history:

    • 1.1 2020 Maintenance
    • 1.0 First live version
    • 0.1 First stub

    CreativeCommonsBy.png This copyrighted material is licensed under a Creative Commons Attribution 4.0 International License. Follow the link to learn more.

    Retrieved from "http://steipe.biochemistry.utoronto.ca/abc/index.php?title=BIN-SX-Molecular_forcefields&oldid=11791"