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Coupling ReaxFF and DREIDING to Coupling ReaxFF and DREIDING to Model Enzymatic Reactions Model Enzymatic Reactions Li Tao, Markus J. Buehler and Li Tao, Markus J. Buehler and William A. Goddard William A. Goddard Motivation Motivation

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SLIDE 1

Coupling ReaxFF and DREIDING to Coupling ReaxFF and DREIDING to Model Enzymatic Reactions Model Enzymatic Reactions

Li Tao, Markus J. Buehler and Li Tao, Markus J. Buehler and William A. Goddard William A. Goddard

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SLIDE 2

Motivation Motivation

  • Find efficient computational method to model

Find efficient computational method to model reactivity in large biological systems reactivity in large biological systems

  • Existing QM/MM methods can model only a few

Existing QM/MM methods can model only a few pre pre-

  • selected atoms

selected atoms

  • Enzymatic reactions may involve hundreds or

Enzymatic reactions may involve hundreds or thousands of reactive atoms thousands of reactive atoms

  • Not feasible with QM/MM schemes

Not feasible with QM/MM schemes

  • ReaxFF can model much larger regions

ReaxFF can model much larger regions involving several thousands of atoms. involving several thousands of atoms.

  • not practical for entire biological system

not practical for entire biological system

  • 80,000 iterations on 280

80,000 iterations on 280-

  • atom system

atom system

  • DREIDING

DREIDING – – dynamics took 1h 41m dynamics took 1h 41m

  • ReaxFF

ReaxFF – – dynamics took 10h 26m dynamics took 10h 26m

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SLIDE 3

Comparison MM, ReaxFF, QM Comparison MM, ReaxFF, QM

yes months, years 500 QM (DFT) yes 5 days 3,000 ReaxFF no 2 days 100,000 MM (DREIDING) Able to Model Reactivity Estimated Clocktime for 1 ns

(max. # atoms)

Maximum number of atoms

Compromise: Compromise: Hybrid ReaxFF/ MM scheme Hybrid ReaxFF/ MM scheme Allows: Large systems (> 100,000 atoms Allows: Large systems (> 100,000 atoms with ~ 3,000 reactive atoms) with ~ 3,000 reactive atoms)

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SLIDE 4

Coupled ReaxFF and DREIDING Coupled ReaxFF and DREIDING

  • Previous ReaxFF studies

Previous ReaxFF studies

  • n enzymes (
  • n enzymes (subtilisin

subtilisin, , lysozyme) fixed non lysozyme) fixed non-

  • participating atoms

participating atoms

  • This region is important

This region is important

  • Elasticity, conformational

Elasticity, conformational changes, inhibitors changes, inhibitors

  • Treating non

Treating non-

  • active

active region with DREIDING region with DREIDING allows physical forces to allows physical forces to be modeled be modeled

Active Site Substrate Enzyme Localized reaction zone Other regions important too?

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SLIDE 5

Implementation Implementation – – Coupling of force Coupling of force fields using mixed Hamiltonians fields using mixed Hamiltonians

  • CMDF framework allows to assign weights

CMDF framework allows to assign weights

  • Use transition zone of radius

Use transition zone of radius r r t

t

  • “Ghost atoms”

“Ghost atoms”

100% DREIDING 100% ReaxFF 50% ReaxFF, 50% DREIDING Calculated with ReaxFF Ghost atoms (0% ReaxFF) Energy Calculation: Interpolation linearly or smoothly using sine function

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SLIDE 6

The The ModMulti ModMulti Modules Modules New CMDF Modules for code coupling New CMDF Modules for code coupling

  • ModMulti

ModMulti

  • Functions for selecting atoms, assigning

Functions for selecting atoms, assigning weights (linearly and non weights (linearly and non-

  • linearly)

linearly)

  • ModRestraints

ModRestraints

  • Functions for driving reactions using restraints

Functions for driving reactions using restraints (see next slide) (see next slide)

  • OBtools

OBtools

  • Utility functions

Utility functions

  • File output in BGF format

File output in BGF format

  • Manipulating X

Manipulating X OpenBabel OpenBabel objects

  • bjects
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SLIDE 7

Implementation Implementation -

  • Coupling

Coupling

Pure ReaxFF Transition Region Pure DREIDING Ghost atoms assignsphere_ w eights( ) function

  • Regions selected

Regions selected using python using python functions functions

  • Overlapping

Overlapping weights for bigger weights for bigger regions regions

  • Regions can be

Regions can be reassigned as reassigned as reaction progresses reaction progresses

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SLIDE 8

Implementation Implementation -

  • Restraints

Restraints

  • Bond restraints

Bond restraints – – keep distances keep distances between two atoms at specified between two atoms at specified equilibrium distance equilibrium distance

  • Equilibrium distance can change

Equilibrium distance can change linearly over time to drive reactions linearly over time to drive reactions

  • Angle restraints

Angle restraints – – control angle control angle between three atoms between three atoms

r θ

( )

( )

u e k f

eq

r r k

v

2 2

1

1 −

− =

Why - Chemical reactions occur slowly at room temperature (biology) MD currently limited to nanoseconds – Chemical reactions need to be assisted to overcome barrier A B Energy Barrier Bond Restraint Angular Restraint

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SLIDE 9

Wave propagation Wave propagation

  • Apply sudden jolt to

Apply sudden jolt to end of C end of C80

80H

H162

162 chain

chain

  • Wave propagated

Wave propagated through ReaxFF region through ReaxFF region

  • Demonstrates

Demonstrates seamless coupling seamless coupling

2.0 ps 4.0 ps 6.0 ps Strain on each carbon Pure Reax Transition Ghost

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SLIDE 10

Single molecule tensile test: Single molecule tensile test: Stretching a C Stretching a C80

80H

H162

162 chain

chain

  • Apply forces to a hydrocarbon chain to investigate

Apply forces to a hydrocarbon chain to investigate how the chain breaks how the chain breaks

  • Relationship between temperature and breaking strain

Relationship between temperature and breaking strain

  • Ensure coupling is done correctly

Ensure coupling is done correctly

  • Same weights as before: 15 carbon atoms in

Same weights as before: 15 carbon atoms in Reax Reax, , 10 A transition zone 10 A transition zone

Pure ReaxFF Transition and Ghost Pure DREIDING F F ReaxFF Atomistic model: Transition and Ghost

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SLIDE 11

Results Results

  • Strain for breakage decreases with

Strain for breakage decreases with temperature temperature

1.08 1.1 1.12 1.14 1.16 1.18 1.2 1.22 1.24 1.26 1.28 100 200 300 400 500 600 700

Temperature vs. Breaking Strain Temperature (K) Breaking Strain

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SLIDE 12

Modeling a Simple Reaction Modeling a Simple Reaction

Number of steps System Energy (kcal/mol) Initial State Transition State End State ~10kcal

C80H161 O- O H O H C80H161 O O H O H

C80H161 O O H O H

  • System energy
  • Moving Average
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SLIDE 13

Summary Summary

  • Have achieved coupling of ReaxFF and

Have achieved coupling of ReaxFF and DREIDING DREIDING

  • Demonstrated coupling by propagating

Demonstrated coupling by propagating waves through the molecule waves through the molecule

  • Applied this method to modeling breaking

Applied this method to modeling breaking strain of single C strain of single C80

80H

H162

162 molecule as a

molecule as a function of temperature. function of temperature.

  • New method allows coupling ~ 3,000

New method allows coupling ~ 3,000 reactive atoms with 100,000 nonreactive reactive atoms with 100,000 nonreactive atoms atoms

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SLIDE 14

Modeling Enzymatic Modeling Enzymatic Activity of Activity of Subtilisin Subtilisin

Number of atoms treated by Number of atoms treated by ReaxFF: 1210 (ca. 30%) ReaxFF: 1210 (ca. 30%) Entire: 3933 Entire: 3933

  • Test coupling of force fields

Test coupling of force fields

  • n biological system
  • n biological system
  • Subtilisin

Subtilisin is a serine protease is a serine protease from bacteria from bacteria

  • Active site consists of

Active site consists of catalytic triad (Ser, His, Asp) catalytic triad (Ser, His, Asp)

  • Entire system of 4,000 atoms

Entire system of 4,000 atoms

  • Too large for pure

Too large for pure ReaxFF ReaxFF

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SLIDE 15
  • 77300
  • 77275
  • 77250
  • 77225
  • 77200
  • 77175
  • 77150
  • 77125

Energy Moving average (150 points)

Step1 Step2 Step3 Step4 Step5 Step6

Energy (kcal/mol)

Procedure for Modeling Enzymatic Procedure for Modeling Enzymatic Activity of Activity of Subtilisin Subtilisin

  • Minimize energy, then

Minimize energy, then equilibriate equilibriate system at 300 K system at 300 K

  • Model each reaction step using restraints to drive.

Model each reaction step using restraints to drive.

  • Our case: First step

Our case: First step – – Transfer proton from serine to Transfer proton from serine to histidine histidine

  • Compare energy barriers with pure ReaxFF and QM results

Compare energy barriers with pure ReaxFF and QM results

Reaction coordinate (Pure ReaxFF)

O H H H N O NH O2N N N H Asp O- O H H His Ser H2C O H

Step 1 – Proton Transfer

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SLIDE 16

Conclusion and Outlook Conclusion and Outlook

  • Possible alternative to QM/MM methods,

Possible alternative to QM/MM methods, but simpler to use and much faster but simpler to use and much faster

  • Coupled calculations are more efficient

Coupled calculations are more efficient than pure ReaxFF (tradeoff) than pure ReaxFF (tradeoff)

  • Possibly useful for quick scanning of

Possibly useful for quick scanning of reaction pathways reaction pathways

  • Designing enzyme with improved enzymatic

Designing enzyme with improved enzymatic activity activity

  • Understanding biological mechanisms

Understanding biological mechanisms

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SLIDE 17

Acknowledgements Acknowledgements

  • Markus J. Buehler

Markus J. Buehler

  • Adri

Adri van van Duin Duin

  • CMDF group

CMDF group

  • William A. Goddard

William A. Goddard

  • Caltech SURF program

Caltech SURF program

  • DARPA PROM for CMDF funding

DARPA PROM for CMDF funding