Methods and apparatus for double-integration orthogonal space tempering

Patent metadata

Field	Value
Publication number	US-2018285534-A1
Application number	US-201815981528-A
Country	US
Kind code	A1
Filing date	May 16, 2018
Priority date	Jun 14, 2011
Publication date	Oct 4, 2018
Grant date	—

Abstract

The orthogonal space random walk (OSRW) algorithm is generalized to be the orthogonal space tempering (OST) method via the introduction of the orthogonal space sampling temperature. Moreover, a double-integration recursion method is developed to enable practically efficient and robust OST free energy calculations, and the algorithm is augmented by a novel θ-dynamics approach to realize both the uniform sampling of order parameter spaces and rigorous end point constraints. In the present work, the double-integration OST method is employed to perform alchemical free energy simulations, specifically to calculate the free energy difference between benzyl phosphonate and difluorobenzyl phosphonate in aqueous solution, to estimate the solvation free energy of the octanol molecule, and to predict the nontrivial Barnase-Barstar binding affinity change induced by the Barnase N58A mutation. As demonstrated in these model studies, the DI-OST method can robustly enable practically efficient free energy predictions, particularly when strongly coupled slow environmental transitions are involved.

First claim

1 . A computer-implemented method for identifying one or more potentially therapeutic drug candidates by simulating systems of molecules through molecular dynamics, the method comprising:
initializing a molecular dynamics engine in a first CPU or GPU; initializing an orthogonal space tempering (OST) engine in a second CPU or GPU, wherein the first CPU or GPU is independent of the second CPU or GPU; at each of a plurality of propagation steps of the molecular dynamics engine;
determining, by the orthogonal space tempering (OST) engine, an alchemical free energy of a system comprising one or more ligands and a specific receptor in an orthogonal space by performing orthogonal space tempering utilizing a second-order generalized ensemble, wherein the second-order generalized ensemble is a generalized orthogonal space random walk (OSRW) method having an effective sampling boundary imposed by a pre-selected orthogonal space sampling temperature (T ES ) and described by a modified energy function as

U
m

=

U
o



(
λ
)

+

f
m



(
λ
)

+

T
ES

-

T
0

T
ES



g
m



(

λ
,

F
λ

)

where λ is an alchemical order parameter, U O (λ) stands for a hybrid energy function that is constructed on the basis of the constraints of U 0 (0)=U A and U 1 (0)=U B , wherein two ends states A and B are respectively represented by λ=1 and λ=0,f m (λ) is adaptively updated to approach −G 0 (λ), g m (λ,F λ ) is adaptively updated to approach −G O (λ,F λ ) and the contribution of g m (λ,F λ ) is scaled by a parameter

(

T
ES

-

T
0

)

/

T
ES

,

wherein T 0 is a system reservoir temperature and T ES is a preset parameter referred to as the orthogonal space sampling temperature;
determining, by the orthogonal space tempering (OST) engine one or more forces between the one or more ligands and the specific receptor based upon the alchemical free energy of the system;
providing the one or more forces to the molecular dynamics engine to accelerate the speed of the structural change of the one or more ligands to overcome one or more free energy barriers in the orthogonal space;

predicting one or more chemical state related thermodynamic properties of the system based upon the determined alchemical free energy of the system; and
identifying one or more potentially therapeutic drug candidates by identifying one or more ligands that are most likely to bind strongly to the specific receptor based upon the predicted one or more chemical state related thermodynamic properties of the system.

2 . The method according to claim 1 , wherein performing orthogonal space tempering further comprises, performing double-integration recursion.

3 . The method according to claim 2 , wherein:
the double-integration recursion is based on dynamic reference restraining.

4 . The method according to claim 1 , wherein:
the method further provides an output selected from the group consisting of, a molecular trajectory and the alchemical free energy of the system.

5 . An apparatus for one or more potentially therapeutic drug candidates, the apparatus comprising:
a molecular dynamics engine in a first CPU or GPU; an orthogonal space tempering (OST) engine in a second CPU or GPU, wherein the first CPU or GPU is independent of the second CPU or GPU; at each of a plurality of propagation steps, the orthogonal space tempering (OST) engine configured to:
determine an alchemical free energy of a system comprising one or more ligands and a specific receptor in an orthogonal space by performing orthogonal space tempering utilizing a second-order generalized ensemble, wherein the second-order generalized ensemble is a generalized orthogonal space random walk (OSRW) method having an effective sampling boundary imposed by a pre-selected orthogonal space sampling temperature (T ES ) and described by a modified energy function as

U
w

=

U
o



(
λ
)

+

f
m



(
λ
)

+

T
ES

-

T
0

T
ES



g
m



(

λ
,

F
λ

)

where λ is an alchemical order parameter, U O (

Assignees

• Univ Florida State Res Found Inc

Inventors

• Yang Wei
• Zheng Lianqing

Classifications

• G06F19/706

  Physics · mapped topic

• G06F19/12

  Physics · mapped topic

• G06F19/701 Primary

  Physics · mapped topic

• G16B5/30

  Dynamic-time models · CPC title

• G16C20/90

  Programming languages; Computing architectures; Database systems; Data warehousing · CPC title