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Questions. Blue should have been covered in lecture. If you still have questions. Please,Ask!. 1) Are the values of r0/theta0 approximately what is listed in the book (in table 3.1 and 3.2)? -> for those atom pairs/triplets yes;

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Questions

Questions

Blue should have been covered in lecture. If you still have questions. Please,Ask!

  • 1) Are the values of r0/theta0 approximately what is listed in the book (in table 3.1 and 3.2)? ->for those atom pairs/triplets yes;

  • 2) In the equations listed for 3.5, what is the j? Is that just the coordinate in space? -> it’s the monomer unit:

  • 3)What exactly is the AMBER program used for? -> MD, minimization and free energy calculations; we will be using other programs

  • 4) Topological Restraints-if the are key in mainting a well defined structure, how come they have been "ignored" in all the calculations we've seen so far. The book is slightly dated

  • In section 3.1.2, the text speaks of the "potential energy due to rotation around the valence cone." ...what is a valence cone? ->see figure 1.3, and the lab; these are torsions

  • 6) Re-explain what the high T approximation is used for and why. I don't remember now, for some reason?

  • 7) What is the AMBER program and how does it arrive at its values?

  • 8) I think there is something wrong with equation (3.5) because I think it should be

  • xj=rcos(2*pi*j*p/P+phi0)and yj=rsin(2*pi*j*p/P+phi0),because P>p from textbook. You are correct; this is a typo.

  • 9) Explain Ep in equation (3.4)?


Questions

Moleculardynamics/mechanics programs

We will use these in lab:

They are used to:

Model protein structures

Study protein folding {with more approximations/”tricks”}

Calculate free energy changes {with more “tricks”}

Calculate protein energetics

Simulate conformational flexibility

Occasionally, study protein dynamics

Examine motional correlations across a protein

Study binding events

Do thought experiments

Use the force fields to do their work, in conjunction with

Optimization routines: minimization -> very hard 3N-6/3N-3 PES; N >1000

Solving Newton’s equations of motions; possibly with restraints/constraints and extra

degrees of freedom

Monte Carlo


Questions

Force Fields

Potential energy terms used to determine the energies and forces during dynamics

There have been changes in the way most forcefields are computed since

Daune was first published

Many different force fields in existence

Some are designed for organic molecules, some for biomolecules, some for

both. Some for different types of calculations.

CHARMM22/27 and AMBER force fields are the most commonly used for biomolecules

Force fields vary in complexity, but CHARMM and AMBER are similar.

Force field in this context is short for all-atom force field.


Questions

Force Fields

Potential energy terms used to determine the energies and forces during dynamics

There have been changes in the way most forcefields are computed since

Daune was first published

Force fields have to be determined self-consistently; see paper

Balance different types of interactions: nonbonded vs bonded; solute-solute,

Solvent-solvent and solvent-solute interactions

Use experimental data on connectivity; supplemented by ab initio calculations

Back-check a proposed set of parameters with MD simulations and minimizations,

and fiddle with the parameters until the results are consistent

Use the simplest set of functions to reproduce physics, and structural properties


Bonds

Bonds

Harmonic Potential

Only good for small vibrations

CANNOT be used to study bond-breaking

Parameters can be obtained from experiments {often}, or from QM calculations

Examples:

CA CA 305.000 1.3750 from experiments on benzene

CT1 C 250.000 1.4900 from 6-31G/HF calculations on ala dipeptide


Bonds1

Bonds

Cubic and higher terms are used in some force fields designed for small molecules. Especially, the MMFF force field which is well-parameterized for many organic molecules.

Morse could allow for bond-breaking; but it would be long-timescale, and expensive

Morse term has been used in conjuction with standard force fields

to study particular bonds; simulate at various points along the morse oscillator to

“integrate” over the other degrees of freedom


Angle interactions

Angle Interactions

Harmonic Potential

Most common form

For a wide range of angles, this term is not enough!

Parameters can be obtained from experiments {often}, or

from QM calculations

Examples:

CA CA CA 40.000 120.00 from experiments on benzene

HB CT1 C 50.000 109.5000 from 6-31G/HF calculations on ala dipeptide


Angle interactions1

Angle Interactions

Harmonic Potential

Most common form

For a wide range of angles, this term is not enough!

Parameters can be obtained from experiments {often}, or

from QM calculations

Examples:

CA CA CA 40.000 120.00 from experiments on benzene

HB CT1 C 50.000 109.5000 from 6-31G/HF calculations on ala dipeptide


Angle interactions urey bradley

Angle Interactions: Urey-Bradley

Often too floppy for ring compounds

For a subset of angles add, a Urey-Bradley term

r

Examples:

CA CA CA 40.000 120.00 35.00 2.41620

HB CT1 C 50.000 109.5000


Bond angle interactions

Bond/Angle interactions

When fitting a potential energy surface experimentally or computationally,

Usually need bond/angle and bond/bond terms

And more complex forms {stretch/bend/stretch}. Usually ignored in biomolecules.


Dihedral interactions

Dihedral interactions

Torsions are usually represented by a series:

Often reduces to a single term.

There can in principle be cross-terms with angles and/or dihedrals: often when fitting potential surfaces, but rarely used in biomolecular force fields.

The next version of the CHARMM force field will include phi/psi cross-terms {for at least some amino acids} to properly balance helical forms


Bonded interactions

Bonded Interactions

The interactions discussed thus far are the “bonded interactions”. They

are used to mimic chemical connectivity.


Nonbonded interactions

NonBonded Interactions

There are two sets of nonbonded interactions: electrostatics and van der

Waals. Almost all pairs of atoms are involved in both interactions.

Note: the sums exclude atoms connected by angles, or bonds {some FF

also exclude dihedrals} This does imply that FF dihedrals are not exactly the

same as dihedrals from experimentalists


Charge interactions

Charge interactions

QM calcs are the starting points for charges; atom-centered monopole fits

to the electrostatic potential of a model molecule {note two approx here}

Charges are commonly modified as part of the iterative fitting; the approximate

fits to QM potential do not reflect the environment found in proteins {or even

in solvent}

Some rare force fields use atom-based multipoles

3rd generation force fields will allow for polarizability


Nonbonded interactions1

Nonbonded Interactions

Vdw parameters are typically considered

as the size of the atom, and the strength

of interaction. However,hydrogens are shrunk

The pairs of parameters are often too many to fit, so a further approximation is:

The vdW parameters are fit , with charges, to reproduce

hydrogen bonds. So the vdW interactions include parts of

H-bonds and dihedrals {steric repulsion}

Leaving fewer parameters to fit iteratively, along with the charges {and

Sometimes dihedrals}.

What has happened to hydrogen bonds?


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