BL5203 Molecular Recognition & Interaction

Section D: Molecular Modeling.

Chen Yu ZongDepartment of Computational Science

National University of Singapore Singapore 119260

Second Part

• Computer modeling of molecular interaction.

Forces Involved in Molecular Interactions More info on the web

– Bond stretch– Bond angle bending– Torsion (bond rotation)– Hydrogen bonding– van der Waals interactions– Electrostatic interactions– Empirical solvation free energy

V = bond 1/2Kb (r-req)2 +

Sangle ½ K (-eq)2 +

torsions 1/2 Vn [ 1 + cos(n-') ] + H bonds [ V0 (1-e-a(r-r0) )2 - V0 ] +

non bonded [ Aij/rij12 - Bij/rij

6 + qiqj /r rij] +

atoms i i Ai

Conformation optimization for molecular interaction

Molecular Mechanics Approach:

Other Approaches: Molecular dynamics. • Time-dependent motion trajectory based on

laws of classical physics. • Advantage: "Accurate" dynamics. • Disadvantage: Short-time event only. • Application: "All purpose", most widely used

approach.Curr. Opin. Struct. Biol. 6, 232 (1996).

Other Approaches:

Stochastic Dynamics.• Solvent represented by frictional and

stochastic forces. • Advantage: Large scale motions, simplified

treatment. • Disadvantage: Limited applicability. • Application: Protein transport, Domain

motion, side-chain swing. Ann. Rev. Biochem 53, 263 (1983)

Other Approaches:

Simplified Model Dynamics. • Simplified structure or forces (e.g. HP lattice,

spin glass model). • Advantage: Long time and large scale dynamics. • Disadvantage: Loss of important features. • Application: Protein folding, mechanical

models, solitons. Proc. Natl. Acad. Sci. USA 90, 1942 (1993); 89, 4918

(1992)

Other Approaches:

Energy Landscape Along Motion Pathways. • Generation of motion pathways by bond

rotations.• Molecular mechanics energy analysis. • Advantage: Complete motion trajectories. • Disadvantage: Limited to “straightforward”

motions. • Application: DNA base opening, base flipping

motions.Phys. Rev. E62, 1133-1137 (2000).

Molecular Dynamics:

Basic Assumptions:• Atoms interact with each other by empirical

forces. • Their motions governed by Newton's law.

Molecular Dynamics:

Basic Equations: • Forces = bond stretch + angle bending +

torsion angle distortion + hydrogen bonding + van de Waals + electrostatic forces + hydrophobic + other solvent interactions

• Newton's law: Forces = mass x acceleration

(F=ma)

Molecular Dynamics:

• Initial conditions at time t: r(t), v(t-dt/2)

• Atomic trajectory at t+dt: a(t) = F(r(t))/m v(t+dt/2) = v(t-dt/2) + a(t) dt r(t+dt) = r(t) + v(t+dt/2) dt

Simulation of open "back door" in acetylcholinesterase:

Science 263, 1276 (1994)

Why interested in this protein? • Key role in signal control in nervous system. • Target of Chinese natural product (Qian Ceng Ta).

Nature Struct. Biol. 4, 57-62 (1997)

Simulation of open "back door" in acetylcholinesterase:

Science 263, 1276 (1994)

Special features: • Active site is in a deep and narrow gorge. • Strong electrostatic force attracts substrate

into the gorge.

Simulation of open "back door" in acetylcholinesterase:

Science 263, 1276 (1994)

Question: • How can a substrate and water escape from

the active site?

Pathways for Functionally Important Motions

DNA base flipping mechanism:– Enzyme induced?.– Enzyme captures a transiently opened

base?

X-ray crystallogaphy:– Structural information on both end of

pathway.– The intermediate path remains unclear

Curr. Opin. Struct. Biol. 7, 103 (1997) Cell 82, 9 (1995)  

Mechanism of base flipping

Scenario I: Protein induced flipping?   • Major groove blocked by enzyme, minor groove

pathway?

• May explain why flipped base orients towards minor groove. .

Cell 76, 357-369 (1994)

Cell 82, 9-12 (1995)  

Mechanism of base flipping

Scenario II: Enzyme recognises and traps a transiently flipped base?

Structure 2, 79 (1994).  • Base pair life time comparable to methyltransferase reaction time.• All modelling studies consistently show base opens via major

groove, yet to show how minor groove opening is possible.Proc. Natl. Acad. Sci. USA. 85, 7231 (1988)

J. Biomol. Struct. Dyn. 15, 765 (1998)

 

• Objective:

– Major groove or minor groove pathway? • Enzyme-captured or enzyme-induced flipping?

• Flipping motion and pathway modelling:– Identification of key rotatable bonds whose motions constructive to flipping.– Modelling of collective rotations of all bonds.

• Energy cost of motion.– Energy barrier along pathway computed by standard force fields.

Testing Scenarios by Molecular Modelling

Modelling Strategy

E n erg y b a rrie r a lon g p a th w ayBased on stan d ard en erg y fu n ction s an d force fie ld s

A d ju s tm en t o f b ase o rien ta tionm in im isation of b ase stackin g along p ath way

A lg orith m fo r co llec tive ro ta tiono f b ack b on e b on d s

G eom etric con strain t th at m im icsh elix restorin g forces

K ey ro ta tab le b on d scon s tru c tive to b ase flip p in g

Phys. Rev. E62, 1133-1137 (2000).

Modelling Strategy

Modelling Results on DNA Base Flipping

Energy Barrier for Base Flipping

Phys. Rev. E62, 1133-1137 (2000).

Maximum Extent of Base Flipping Along Both Grooves

System NDB ID Flipped Dmajor dminor

Base (A) (A)

Hhal Mtase GATAGCGCTATC PDEB08 C18 11.89 4.87HhaI MTase CCATGCGCTGAC PDEB123 C18 12.25 3.23Hhal Mtase GTCAGCGCATGG PD0017 A18 11.37 4.42HeaIII Mtase ACCAGCAGGCCACCAGTG PDEB19 C10 12.01 1.23

B-form CCGGCGGCCGG BDL039 C5 12.13 2.13B-form CGCGAATTCGCG BDL001 A5 14.17 1.47B-form ACCGGCGCACA BDL035 C7 12.18 2.02

Phys. Rev. E62, 1133-1137 (2000).