Energy Maintenance for Molecular Simulation

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Energy Maintenancefor Molecular Simulation
kinematics energy ? motion structure
Main computational issue Proximity computation
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Energy
Function defined over large dimensionalconformati
on space
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Energy Function

• E ES EQ ESQ ETor EvdW Edipole

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Energy Function

• E ES EQ ESQ ETor EvdW Edipole

EvdW
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Role of vdW Terms

• vdW terms ? maze of in conformational space
• Other terms steer the molecule in this maze

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Heuristic Energy Terms(e.g., Go Models)
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Interaction with Solvent

• Explicit solvent models 100s or 1000s of
  discrete solvent molecules
• Implicit solvent models solvent as continuous
  medium, interface is solvent-accessible surface

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Energy Function

• E S bonded terms S non-bonded terms
  S solvation terms
• Bonded terms - Relatively few
• Non-bonded terms - Depend on distances between
  pairs of atoms - Quadratic number ? Expensive to
  compute
• Solvation terms- May require computing molecular
  surface

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Energy Function

• E S bonded terms S non-bonded terms
  S solvation terms
• Bonded terms - Relatively few
• Non-bonded terms - Depend on distances between
  pairs of atoms - Quadratic number ? Expensive to
  compute
• Solvation terms- May require computing molecular
  surface

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Uses of Energy Function

• Generate energetically plausible conformations
  sample (at random), minimize, cluster
• Generate meaningful distributions (e.g.,
  Boltzman) of conformations Monte Carlo
  simulation
• Generate motion pathways to study molecular
  kinetics molecular dynamics, MC simulation

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Monte Carlo Simulation (MCS)

• Popular approach to study thermodynamic and
  kinetic properties of proteins
• Random walk through conformation space
• At each cycle
• Perturb current conformation at random
• Accept step with probability
• (Metropolis acceptance criterion)
• The conformations generated by an arbitrarily
  long MCS are Boltzman distributed, i.e.,
  conformations in V

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Uses of Energy Function

• Generate energetically plausible conformations
  sample (at random), minimize, cluster
• Generate meaningful distributions (e.g.,
  Boltzman) of conformations Monte Carlo
  simulation
• Generate motion pathways to study molecular
  kinetics molecular dynamics, MC simulation
• ? One issue in common Energy must be evaluated
  frequently E.g., MD and MC simulation runs may
  consist of millions of steps, each

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Uses of Energy Function

• Generate energetically plausible conformations
  sample (at random), minimize, cluster
• Generate meaningful distributions (e.g.,
  Boltzman) of conformations Monte Carlo
  simulation
• Generate motion pathways to study molecular
  kinetics molecular dynamics, MC simulation
• ProblemHow to efficiently compute and update
  energy during minimization and simulation?

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Non-Bonded Energy Terms

• Quadratic number of pairs of atoms
• Energy terms go to 0 when distance increases ?
  Cutoff distance (6 - 12Å)
• vdW forces prevent atoms from bunching up ?
  Only O(n) interacting pairs
  HalperinOvermars 98
• Problems
• How can we find the interacting pairs without
  enumerating all atom pairs?
• How can we detect atomic clashes quickly?
• Main computational issue Proximity computation

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Grid Method

• Subdivide 3-space into cubic cells
• Compute cell that contains each atom center
• Represent grid as hashtable

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Grid Method

• O(n) time to build grid
• O(1) time to find interactive pairs for each atom
• T(n) to find all interactive pairs of atoms
  HalperinOvermars, 98
• Asymptotically optimal in worst-case

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Energy Update

• Compare the interacting pairs at new step with
  those at previous step
• For every pair that has disappeared, subtract the
  corresponding energy term from energy value
• For every new pair, add the corresponding energy
  term to energy value
• Takes T(n) time, even if very few pairs have
  changed

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The grid method is unable to recognize and re-use
such partial sums
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Grid Method

• O(n) time to build grid
• O(1) time to find interactive pairs for each atom
• T(n) to find all interactive pairs of atoms
  HalperinOvermars, 98
• Asymptotically optimal in worst-case
• But
• - Energy partial sums?
• - Atomic clashes?
• second grid with small cutoff distance

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Grid Method ? Surface Halperin and Shelton, 97

• Each sphere intersects O(1) spheres
• Computing each atoms contribution to molecular
  surface takes O(1) time
• Computation of molecular surface takes T(n) time
• ? implicit solvation term in T(n) time

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General Problem

• Molecules form geometrically complex objects that
  deform and move relative to each other
• (Self-)collision detection
• Distance computation

• Several computational approaches
• Space occupancy grid, octree
• Tracking pairs of closest features
• Polynomial equation
• Bounding-volume hierarchies (BVH)
• Spanners

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Bounding Volume Hierarchies (BVHs)

• Outline
• Case of rigid objects
• Bounding volume (BV)
• BV hierarchy (BVH)
• Types of BVs
• Collision detection with BVHs
• Distance computation
• Application to deformable objects
• Application to protein simulation

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Basic Problem

• Given the geometric models and relative positions
  of two objects, determine whether they overlap

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Basic Problem

• Given the geometric models and relative positions
  of two objects, determine whether they overlap

distance 0 ? collision
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Applications

• Computer graphics simulation
• Robotics
• Haptics

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Basic Idea of Solution

• Enclose objects into bounding volumes (spheres
  or boxes)
• Check the bounding volumes first

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Basic Idea of Solution

• Enclose objects into bounding volumes (spheres
  or boxes)
• Check the bounding volumes first
• Decompose an object into two

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Basic Idea of Solution

• Enclose objects into bounding volumes (spheres
  or boxes)
• Check the bounding volumes first
• Decompose an object into two
• Proceed hierarchically

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Basic Idea of Solution

• Enclose objects into bounding volumes (spheres
  or boxes)
• Check the bounding volumes first
• Decompose an object into two
• Proceed hierarchically

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Bounding Volume Hierarchy (BVH)

• BVH is pre-computed for each object
• BVH is typically a balanced binary tree

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BVH in 3D
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Collision Detection
Two objects described by their precomputed BVHs
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Collision Detection
Search tree
AA
A
A
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Collision Detection
Search tree
AA
A
A
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Collision Detection
Search tree
AA
CC
CB
BC
BB
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Collision Detection
Search tree
AA
CC
CB
BC
BB
G
D
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Variant
Search tree
A
A
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Collision Detection

• Pruning discards subsets of the two objects that
  are separated by the BVs
• Each path is followed until pruning or until two
  leaves overlap
• When two leaves overlap, their contents are
  tested for overlap

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Search Strategy and Heuristics

• If there is no collision, all paths must
  eventually be followed down to pruning or a leaf
  node
• But if there is collision, it is desirable to
  detect it as quickly as possible
• ? Greedy best-first search strategy with f(N)
  d/(rXrY) Expand the node XY with
  largest relative overlap (most likely to
  contain a collision)

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Recursive (Depth-First) Collision Detection
Algorithm

• Test(A,B)
• If A and B do not overlap, then return 1
• If A and B are both leaves, then return 0 if
  their contents overlap and 1 otherwise
• Switch A and B if A is a leaf, or if B is bigger
  and not a leaf
• Set A1 and A2 to be As children
• If Test(A1,B) 1 then return Test(A2,B) else
  return 0

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Performance

• Several thousand collision checks per second for
  2 three-dimensional objects each described by
  500,000 triangles, on a 1-GHz PC

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Greedy Distance Computation(same recursion as
collision detection)

• Greedy-Distance(A,B)
• If dist(A,B) gt 0, then return dist(A,B)
• If A and B are both leaves, then return distance
  between their contents
• Switch A and B if A is a leaf, or if B is bigger
  and not a leaf
• Set A1 and A2 to be As children
• d1 ? Greedy-Distance(A1,B)
• If d1 gt 0 then
• d2 ? Greedy-Distance(A2,B)
• If d2 gt 0 then return Min(d1,d2)
• Return 0

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Exact Distance Computation
M (upper bound on distance) is initialized to
very large number

• Distance(A,B)
• If dist(A,B) gt M, then return M
• If A and B are both leaves, then
• d ? distance between their contents
• Return Min(d,M)
• Switch A and B if A is a leaf, or if B is bigger
  and not a leaf
• Set A1 and A2 to be As children
• M ? Distance(A1,B)
• If M gt 0 then return Distance(A2,B)
• Else return 0

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Approximate Distance Computation
M (upper bound on distance) is initialized to
very large number

• Approx-Distance(A,B) ? da da ? de and de-da ?
  ade
• If dist(A,B) gt M, then return M
• If A and B are both leaves, then
• d ? distance between their contents
• If d lt M then return (1-a)?d else return M
• Switch A and B if A is a leaf, or if B is bigger
  and not a leaf
• Set A1 and A2 to be As children
• M ? Approx-Distance(A1,B)
• If M gt 0 then return Approx-Distance(A2,B)
• Return 0

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Approximate Distance Computation
M (upper bound on distance) is initialized to
very large number

• Approx-Distance(A,B) ? da da ? de and de-da ?
  ade
• If dist(A,B) gt M, then return M
• If A and B are both leaves, then
• d ? distance between their contents
• If d lt M then return (1-a)?d
• Switch A and B if A is a leaf, or if B is bigger
  and not a leaf
• Set A1 and A2 to be As children
• M ? Approx-Distance(A1,B)
• If M gt 0 then return Approx-Distance(A2,B)
• Return 0

Garanteed to return an approximate distance
between (1-?)d and d
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• Collision detection
• lt Greedy distance computation
• lt 0.5 Approximate distance computation
• ltlt Exact distance computation
• lt slightly faster
• ltlt much faster

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Desirable Properties of BVs and BVHs

• BVs
• Tightness
• Efficient testing
• Invariance

• BVH
• Separation
• Balanced tree

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Desirable Properties of BVs and BVHs

• BVs
• Tightness
• Efficient testing
• Invariance

• BVH
• Separation
• Balanced tree

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Spheres

• Invariant
• Efficient to test
• But tight?

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Axis-Aligned Bounding Box (AABB)
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Axis-Aligned Bounding Box (AABB)

• Not invariant
• Efficient to test
• Not tight

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Oriented Bounding Box (OBB) Gottschalk, Lin,
and Manocha, 96
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Oriented Bounding Box (OBB)

• Invariant
• Less efficient to test
• Tight

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Rectangle Swept Spheres (RSS)

• Similar to OBBs

? Efficient distance computation
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Computation of Distance Between Two RSSs

• Compute the distance between the two underlying
  rectangles
• Subtract the growing radius

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Comparison of BVs
No type of BV is optimal for all situations
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Computation of a BV Sphere

• Each intermediate sphere encloses the geometry
  contained in its descendant leaf nodes
• Simple solution Compute each intermediate sphere
  to minimally enclose its two children
• Tighter-fitting solution each intermediate
  sphere is computed to minimally enclose the
  spheres leaf descendants Welzl, 91 ? expected
  O(N) time

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Computation of an OBBGottschalk, Lin, and
Manocha, 96

• N points ai (xi, yi, zi)T, i 1,, N
• SVD of A (a1 a2 ... aN)
• ? A UDVT where
• D diag(s1,s2,s3) such that s1 ? s2 ? s3 ? 0
• U is a 3x3 rotation matrix that defines the
  principal axes of variance of the ais ? OBBs
  directions
• The OBB is defined by max and min coordinates of
  the ais along these directions
• Possible improvements use vertices of convex
  hull of the ais or dense uniform sampling of
  convex hull

rotation described by matrix U
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OBB of a Collection of Spheres

• Compute the OBB of the centers
• Grow the OBB by moving each of its faces
  outwardby the atom radius

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Computation of an RSSLarsen, Gottschalk, Lin,
and Manocha, 00

• Similar to OBB. Compute the two principal axes of
  variance of the ais (atom centers)
• Project all ais into the plane P defined by
  these two directions
• Compute minimum enclosing rectangle R contained
  in P and aligned with these directions
• Grow R by half the length of the interval spanned
  by the ais along the direction perpendicular to
  P increased by the atom radius

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Desirable Properties of BVs and BVHs

• BVs
• Tightness
• Efficient testing
• Invariance

• BVH
• Separation
• Balanced tree

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Desirable Properties of BVs and BVHs

• BVs
• Tightness
• Efficient testing
• Invariance

• BVH
• Separation
• Balanced tree

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Construction of a BVH

• Top-down recursive algorithm from the root to the
  leaves
• At each step, create the two children of a BV

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Subdivision of a Sphere BV

• Split longest axis of AABB at mid or median point
• Median point guarantees balanced BVH, but takes
  slightly more time to compute

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Subdivision of an OBB/RSS

• Split longest axis at mid or median point

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Application to Deformable Objects

• The BVH computed for some initial or nominal
  geometry may become useless

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Application to Deformable Objects

• The BVH computed for some initial or nominal
  geometry may become useless
• ? Group pieces hierarchically based on
  topological rather than geometric proximity
• Topological proximity is
• invariant
• implies geometric proximity (converse is not true)

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Particular Case Long Chain
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Application to Deformable Objects

• The BVH computed for some initial or nominal
  geometry may become useless
• ? Group pieces hierarchically based on
  topological rather than geometric proximity
• Topological proximity is
• invariant
• implies geometric proximity (converse is not
  true)
• ? BVH with fixed topology, but BVs must still be
  adjusted in size and position
• Self-collision detection is done by testing a BVH
  against itself

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Particular Case Long Chain

• A chain of spheres is well-behaved iff
• The ratio of the radii of the largest and
  smallest spheres is less than some g
• The distance between any two spherecenters is
  greater than some d

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Application to Monte Carlo Simulation of
Proteins(ChainTree)
I. Lotan, D. Halperin, F. Schwarzer and J.C.
Latombe. Algorithm and Data Structures for
Efficient Energy maintenance During Monte Carlo
Simulation of Proteins, J. Computational Biology,
2004
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Monte Carlo Simulation (MCS)

• Random walk through conformation space
• At each cycle
• - Perturb current conformation at random
• Accept step with probability
• Problem Update energy value

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Energy Function

• E S bonded terms S non-bonded terms
  S solvation terms
• Bonded terms - Relatively few
• Non-bonded terms - Depend on distances between
  pairs of atoms - Quadratic number ? Expensive to
  compute
• Solvation terms- May require computing molecular
  surface

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Non-Bonded Energy Terms

• They go to 0 when distance increases ? Use
  cutoff distance (6 - 12Å)
• vdW forces prevent atoms from bunching up ? Only
  O(n) interacting pairs HalperinOvermars 98

Problem How to find these interacting pairs
without enumerating all atom pairs?
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Can We Do Better on Average than Grid method?

• Few DOFs are changed at each MC step

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Can We Do Better on Average than Grid method?

• Few DOFs are changed at each MC step

simulationof 100,000 attempted steps
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Can We Do Better on Average?

• Few DOFs are changed at each MC step
• Proteins are long chain kinematics

• Long sub-chains stay rigid at each step
• Many partial energy sums remain constant

Problem How to retrieve the unchanged partial
sums?
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ChainTree(Twofold Hierarchy BVs Transforms)
links
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ChainTree(Twofold Hierarchy BVs Transforms)
joints
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Updating the ChainTree

• Update path to root
• Recompute transforms that shortcut the DOF
  change
• Recompute BVs that contain the DOF change
• O(k (log(n/k)1)) work for k changes

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Finding Interacting Pairs
??
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Finding Interacting Pairs
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Finding Interacting Pairs

• Do not search inside rigid sub-chains (unmarked
  nodes)
• Do not test two nodes with no marked node between
  them

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Finding Interacting Pairs

• Do not search inside rigid sub-chains (unmarked
  nodes)
• Do not test two nodes with no marked node between
  them

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EnergyTree
E(N,N)
E(K.L)
E(M,M)
E(L,L)
E(J,L)
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EnergyTree
E(N,N)
E(K.L)
E(M,M)
E(L,L)
E(J,L)
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Computational Complexity

• n total number of DOFs
• k number of DOF changes at each MCS step
• k ltlt n
• Complexity of
• updating ChainTree O(k (log(n/k)1))
• finding interacting pairs O(n4/3) but performs
  much better in practice!!!

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Experimental Setup

• Energy function
• Van der Waals
• Electrostatic
• Attraction between native contacts
• Cutoff at 12Å
• 300,000 steps MCS with Grid and ChainTree
• Steps are the same with both methods
• Early rejection for large vdW terms

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Results 1-DOF change
12.5
7.8
speedup
5.8
3.5
amino acids
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Results 5-DOF change
5.9
speedup
4.5
3.4
2.2
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Two-Pass ChainTree (ChainTree)
1st pass small cutoff distance to detect steric
clashes 2nd pass Normal cutoff distance
Tests around native state
gt5
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Interaction with Solvent

• Explicit solvent models 100s or 1000s of
  discrete solvent molecules
• Implicit solvent models solvent as continuous
  medium, interface is solvent-accessible surface

E. Eyal, D. Halperin. Dynamic Maintenance of
Molecular Surfaces under Conformational Changes.
http//www.give.nl/movie/publications/telaviv/EH0
4.pdf
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Conclusion

• ChainTree significantly reduces average time of
  MCS for proteins (vs. grid)
• It exploits
• Atomic exclusion
• Cutoff distance on potentials
• Chain kinematics of protein
• Small of DOF changes at each MC step
• Larger speed-up for bigger proteins and smaller
  of simultaneous DOF changes
• Extension to updating protein surface
• http//robotics.stanford.edu/itayl/mcs

Already exploitedby grid method