Pula

April 21, 2008

FlexCryst: A tool for molecular simulations FlexCryst: A tool for molecular simulations

in biochemistry and crystallographyin biochemistry and crystallography

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FlexCryst: A tool for molecular simulations in biochemistry and FlexCryst: A tool for molecular simulations in biochemistry and crystallography (D.W.M. Hofmann, 21 April 2008, 10:30)crystallography (D.W.M. Hofmann, 21 April 2008, 10:30)

Abstract: In this talk we present FlexCryst: Flexcryst is a program suite with a graphical user interface (GUI). Presently it contains 6 modules, ligand receptor docking, crystal structure prediction, crystal structure determination, sublimation energy of crystal structures, and comparison of powder diagrams. Main feature of the modules is the high velocity. This is connected with the selected approach: all modules are based on classical mechanics and take only short range interaction into account. The energy function has been optimized by data on the largest existing database of crystal structures, the Cambridge Structure Database (CSD). The mean error of the energy function has been tested by prediction of the sublimation energy of more than 100 crystal structures and has been found to be around 7 KJ/mole. The energy function was applied to the problem of ligand-receptor docking in collaboration with BiosolveIt. It shows better scoring for small shifts of the ligands, however it is less tolerant to large shifts. A further advantage of the trained energy function is that it gives real bonding energies rather than arbitrary scores.

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Main features of FlexCryst

consists of 6 independent modulesbases on classical mechanicsscoring function evaluates very quicklymolecules are treated as rigidscoring function predicts well sublimation energiesa graphical user interface is available common input formats are supported

OverviewOverview

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Converting of Data FormatsConverting of Data Formats

Supported input formats:

• CIF (.cif) Crystallographic Information File (CIF) format -- International Union of Crystallography format for crystal structure data.

• CSSR (.cssr) SERC Daresbury Laboratory's Cambridge Structure Search and Retrieval (CSSR) file format.

• PDB (.pdb) Protein Data Bank format for 3D molecules.

• Mol2 (.mol2) Tripos Mol2 File Format

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Pula, 21 April 2008

EIJ [KJ /mole]=∑i=1

nI

∑j=1

n J

type i ,type j , r ij=∑

i=1

nI

∑j=1

n J

mnr ij

The energy function:

fast to evaluate potentials are tabled at auxiliary

points cut off at 5.77 Å

pair potentials are steadypotentials have optimum shape

parameters are optimized by data mining

short term potentials contain long term interactionshydrogen is differentiated in various types

energy function:

auxiliary points (descriptors): K= {kmnl :kmnl=100/ l2 with 3≤l≤60}

pair potential (weights):

mnr ij=f −l mnl l1−f mnl1 with l=⌊f ⌋ and f=100/r ij

2

cutoff: r cutoff=k3=100/32≈5.77 A

example: the H(N)...O potential

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Parametrization by data miningParametrization by data mining

Each experimental structure should be in local minimum of energy (if the structure is correct). Therefore any slightly distorted structure (decoy) must be higher in energy.

2

1

minimum condition: En≤Enme

The error function J (perceptron) measures the distorted structures, which violate the minimum condition.

error function: J = ∑n=1

400000

∑m=1

10

max [0,En−Enme2 ]

Aim of the minimization with neuronal networks or simplex algorithm is to separate as good as possible the decoys and the experimental structures by an hyperplane. The perpendicular vector to this plane contains the parameters of the force field (weights).

frequency of contact type 1(descriptor 1)

freq

uency

of

con

tact

type 2

(desc

rip

tor

2)

The figure shows one experimental structure with ten decoys. The structures are described by two selected types of contacts. Two of the decoys are outliers and can not be separated by the hyperplane (in the two dimensional case it reduces to a line).

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Prediction of sublimation energiesPrediction of sublimation energies

A wide variety of solid substances occurs in crystalline or microcrystalline state (e.g. drugs). One of the most important properties are the sublimation energy. Further properties can be derived from this energy.

The sublimation energy can be estimated with an accuracy of 8.9 KJ/mole, which is correlated to the experimental accuracy. In the database some structures (same color) occur manifoldly with slightly different coordinates. The resulting energy difference determines the mean error.

mean error:

8.9 KJ/mole

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Crystal Structure PredictionCrystal Structure Prediction

experimental structure

simulated structure (rank 2)

Thermodynamical properties can be derived very well, because all high ranking crystal structures have similar energy. The conformation has to be highly accurate All atoms must have ordinary environment The experimental crystal structure can be determined by help of additional information (e.g. powder diagram), because it is found among the first hundred predicted crystal structures.

example: Blind test at Cambridge 2007, Molecule XIV

One unique substance (drug, pigment) can occur in several crystal structures (polymorphs). These different polymorphs have different kinetic properties, as the rate of solubility, and can be patented separately

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Comparing of Crystal StructuresComparing of Crystal Structures

similarity

0.005

Crystal structures and powder diagrams can be compared automatically. The results are visualized in dendrograms. Main applications of it are:

Screening off manifold predictions Search for similar crystal structures Systematizing of powder diagrams Cleaning of data bases

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Crystal Structure DeterminationCrystal Structure Determination

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conformation generation • rigid molecules e.g. drugs and pigments• programs• intuitive

crystal structures generation

conformation optimization DMOL3, Gaussian, and other quantum chemical programs

crystal structure minimization

remove double predicted strutures

scoring and sorting

automatic refinement

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FlexibilityFlexibility

Drugs are very often rigid. Flexible drugs loose during docking degrees of freedom, which comes along with a decrease of the entropy. In result the binding affinity of flexible molecules is lower than for rigid molecules

caffeine (30mg/Espresso)

nicotine (1mg/Cigarette)

progesterone contraception

Clopidogrel antiplatelet

(annual sales 6,057,000 USD)

HproteinHdrug−TSdrug⇔Hcomplex

However, flexible molecules show much more often biological activity and are more practical to find leading structures for drug design. Due to the flexibility they can easier conform themselves to a given pocket of a protein.

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cis-4-octeneC. Schauerte, C. Buchsbaum,L. Fink, D. W. M. Hofmann,M.U. Schmidt, J. Knipping, and R. Boese Acta Cryst. (2005). A61, C290

Pigment Yellow 111

Examples of determined crystal structures from X-ray powder diagrams

Pigment Red 181

D.W.M.Hofmann and L.N.Kuleshova, J. Appl. Cryst. (2005) 38, 861-866.

Crystal Structure DeterminationCrystal Structure Determination

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DockingDocking

The presented scoring function gives the energy for a given ligand-protein complex. This gives access to thermodynamical properties of the complex

In the figure we show a complex generated by FlexX. The receptor is repositioned and the energy of the complex is calculated

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Docking: present stateDocking: present state

The trained force field scores more accurate as common scoring functions and gives the free energy for ligand protein complex rather than an arbitrary score.

In this figure the trained force field is compared to the scoring function implemented in FlexX. For small rmsd the number of correctly predicted complexes is always higher (blue chart). For large rmsd FlexX scores better (violet chart)

nFl

exX-n

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number of ranks taken into account

The high accuracy becomes even more obvious, if the experimental structure is added to the poses. In hits example around 90-times the experimental structure obtains the lowest energy and the rmsd is zero.

rmsd [Å]

num

ber

of

ligand-p

rote

in c

om

ple

x

•trained force field, experimental structure included

•FlexX, experimental structure included•trained force field without experimental structure

•FlexX, without experimental structure•best structure generated

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