CC BY
7Journal of Siberian Federal University. Biology 1 (2014 7) 4-13
УДК 004.42
Calculation of Force Field Grids for Molecular Docking Using Graphics Processing Unit
Mikhail A. Farkov*
Siberian Federal University 79 Svobodny, Krasnoyarsk, 660041, Russia
Received 05.08.2013, received in revised form 13.08.2013, accepted 11.03.2014 The vast majority of problems faced by bioinformatics are very complex and time consuming. They require the use of modern high-performance computational systems and the development of algorithms for such system. Heterogeneous computing systems which include graphics processing unit (GPU) occupy a separate niche. Such systems allow to accelerate solving of some task significantly. The task performing molecular docking namely accelerating the calculation offorce field grids for fast ligand-protein molecular docking is studied in this work. Algorithms for fast calculation of the large number of force field grids which are scaled to all GPUs available in the system were developed. Extensive testing on different platforms was performed.
Keywords: GPGPU, CUDA, molecular docking, virtual screening, ligand-protein docking.
Вычисление сеток силовых полей для молекулярного докинга с использованием графических процессоров
М.А. Фарков
Сибирский федеральный университет Россия, 660041, Красноярск, пр. Свободный, 79
Подавляющее большинство задач, с которыми приходится сталкиваться биоинформатике, чрезвычайно сложны и времязатратны. Для их успешного решения требуется использовать современные высокопроизводительные вычислительные системы, для которых необходимо
© Siberian Federal University. All rights reserved
* Corresponding author E-mail address: mihail.farkov@gmail.com
разрабатывать новые, специфичные алгоритмы. Среди таких систем отдельную нишу занимают гетерогенные вычислительные системы, в состав которых входят графические процессоры. Подобные системы позволяют существенноускорить вычисления некоторыхзадач. В работе представлены алгоритмы, использующие возможности графических процессоров для ускорения молекулярно докинга, а именно для построения сеток силовых поней для услорения молекулярного лиганд-белкового докинга. Предложенные алгоритмы ориентированы на быстрое вычисление большого количества сеток силовых полей и масштабируются на любое доступное компьютеру коллчество графических пркцессорол.
Ключевые слова: GPGPU, CUDA, молекулярный докинг, виртуальный скрининг, лиганд-белковый докинг.
Introduction
The rational drug design is a process that requires much time and financial investments. It takes several years to develop a new drug. The one of the key problems in rational drug design is a selection of perspective candidates in drugs. This peocess can take considerable period of time (1-3 yeara) and vequires significant financial investments for chemicals and complex equipments (Kuntz, 1992). hhe maingoal of this stage is to find some set of molecular compounds for the next stage of development, i.e. preclinical and clinical experiments. Errors at this stage of development can cause enormous losses at the next stages. Molecular dockings is used to overcome the above problems. It is computer modeling of interaction of come molacules. Mnlecular ligand-protein docking is a modeling of interaction of a small molecule candidate in drugs (called ligand) and protein (called biotarget). Molecular docking gives information about principal possibility of reaction between molecules and gives estimates of the energy of the reaction that will be used to select perspective compounds for "in vitro" and "in vivo" experiments. Molecular docking is a quite computationally costly procedure that requires modeling of significant amounts of compounds at different spatial locations. Moreover it is necessary to estimate energy of interactions of the large number of atoms for single compounds.
Thereby for such calculation it is necessary to use high performance computers that contain graphicf pvoceesing units (GPU) which are nery suited for solving of ahe propo sef task.
Program for calculation of force field grids for molecular docking is presented in this paper. Graphics processing units are used in order to get ssseedup for the traditional grids approach. Electrostatic and van der Waals forces are taken inth account.
Methods
The energy of the molecules interaction can be estimated as a linear combination of several componenas fCnrnell et al., 1995; Jones et al., 1997; MacKerell et al., 1998).
Etotal _ Evdw + Eelec + Ebond + Eangle + Etorsion
Evdw is the van der Waals energy (this energy arises between atoms 2 and 5 on Fig. 1); Ee!ec is the electrostatic energy (atoms 1 and 6 on Fig. 1); Ebond is the energy of interaction between two covalently bound atoms (atoms 2 and 3 on Fig. 1); Eangle is the energy of interaction between three covalently bound atoms (atoms 1, 2 and 3 on Fig. 1); Etorsio„ is the energy of interaction between covalently bound atoms that form torsion angle (atoms 1,2,3 and 4 on Fig. 1). These components can be roughly divided into 5 -
Fig. 1. Model of atoms in molecules
two groups: intermolecular and intramolecular interconnections. Ebo„° Eangle_ Etorslo„ are the energies oe intromoleculab interconnections. These types of energies are kind of penalty that indicates that structure of molecule differs from the "ideal" structure , i.e. there aye covalent bonds lengths, covalent and torsion angles thet differ from the "ideal" covalent bonds lengths, covalent and torsion angles between atom types in molecnle. Tlie vab dee Waals and electroytanic energies aro intermolecflar interconnectk)n These types of energies are the main contributors to the total estimation of the energy. In turn, each intremoleculdr cemponent can be calculated as a linent cn mbenation of interaction between each atom of ligand and each atom of biotarget.
The van der Waal s energ}/ is calnulared by using the LennerdJones potential alto known as the 6-12 potential (Goodford, 1985; Jones et al.,1997; Ewinga et al., 2t01; Gilson et al.,200t):
Evdw = 2 si
where e, and r0j are constants, rv is the distance between interacting atoms.
The electrostatic energy is calculated by using the Coultmb's law:
Eeiec = Z(<yae Mj
where e is the permittivity, rv is the distance between interacting atoms, qi,qj are charges of dtnmr.
A common tecnm^ie to accelerate molecular docking is called the grids approach. Biotarget .s placed id some limine d area (e.g. cuboid) and as considered at fixed. Some components of the total energy are calculated for each cell of the grid with some step for each atom type that is presented in n-e ligrnd. Thb pdobe atom type (e.g. hynnogen) ir placed in each cell of the grid and the van der Waals interaction with the biotarget is calsulnted (Fig. 2).
This nan bn done only for intermolecular componenis oe the total energy because these components don't depend on mutual location of the Hgand and the biotarget. The result of the procedure is a set of arids which are used for molecular docking. The same atom types of the explored ligand will be placed at the approximately same points of the area during docking process very oflen. Hence duning docking it is not necessary to repeat the large number of the same type of calculation for different locations of the explored ligand. One can get precalculated value of the energy from the grid for the desired atom type. The grid approach gives extra speedup for flexible ligand-protein docking since it is necensary to use additional internal degrees of dreedom on the liganar for such calculation (it is 6 -
Fig. 2. Example of grid
rotation around covalent bonds and alteration of valence and torsion angles).
Implementanon
There is a set of targets TARGETS at the input of the procedure where each element target is matched to e eet of ligands LIGANDSi wliebe each element ligand^ is matche d to a set oh atom types ATOM_TYPESy such that each atom_typeijk is presented in the ligand at least once. The result of the calculation is a set of grids GRIDS wIere each elemeat gridy is a nesult of the calculation of the grid for atom type k that belongs to ligand j and interacts withbiotarget i. It is true that grids far the same ntom type trom diffeaent ligands tliat interact with the same biotarget are equal, i.e.:
atom_tepes sjk = atom_types lmp — 11™^= Hti(C lnm .
Hence iit is posaiele to reducr the calculafion. Pria-wise calculations oh the grids for enth biotargets targeti from the set TARGETS and each ligand from the set LIGAND St are replaced with calculafions of grid Sor tacee^and atom types that are presented in ligands trom set LIGANDSi at least once.
It is not necessary to calculate grids for each charge in ligands since it is possible to evaluate the electrostatic energy at ghe grid's po int without charges of the ligand because the biotarget is fixed and impacts equally to the points of the are a and it is possible to factor out charge of ligand in the Coulomb's law. As a result it is necessary to caiculate
|Atom_typesi0 u ATOM_TYPES ¡J u...
.. T ATOM__T YPES i(Nt) |+ 1,N := |LIGANDS, | grids for one biotarger.
Two different apptouahes foa calcuration of the permittivity for the Coulomb's iaw aee used in this work. The constant permittivity is used in the first approach. A user sets up the necessary permitgivity and this value is osed duting all calculation. The second approach is the distance dependent approach for evaluation of the permittivity according to rhe distance ietween point of the msid and atoms oD She Eiotarget. The parameters offered by Mehler and Eichele are used in thus work gMehler et af a984; Mehler rt al., 1991)). This appgoach demonstrate n sigaificantly betaer results ctmparable with tbe aeaults of t0e calculations using molecular dynamic. But it
takes a bit more calculation time (benchmarks are presented in the Results chapter).
Information from AMBER99 force field is used as a topology for biotargets. General AMBER force field (GAFF) is used as a resource of parameters for the van der Waals calculation. Typing the ligand molecule is performed with the Antechamber program from the AmberTools package (Wang et al., 2004; Wang et al., 2006).
Calculations of both energy components in each cell of the grid are fully independent. Tasks with such level of data parallelism are very suitable for GPU that has a lot of simple arithmetic logic units (ALU) and is oriented to SIMD programming model. Calculation of a single grid is decomposed between all ALUs of GPU in such way that a single ALU calculates energy in one cell of grid at one moment. The result of the calculation is placed in the grid that represents in GPU memory as one dimension array in such way that the X coordinate is increased most rapidly (Fig. 3). Such decomposition and memory representation guarantee that all requests to global memory will be coalesced and at least N*32 grid's point will be evaluated simultaneously where N is the number of multiprocessor in GPU. The actual number will be greater because of the different number of dispatchers on different GPU architecture.
At the same time calculation of different grids is an independent process too. It allows us to add an additional level of decomposition in
case of several GPUs on one computer. The basic computational unit is a single grid which is fully calculated on the same GPU (Fig. 4). Different grids (even for one biotarget since time for reading the biotarget is short) are dispatched between different appropriate GPUs. Load balancing is performed according to the time complexity of the algorithm. The complexity for the single grid calculation is equal to 0(n*m) where n is the number of cells in the grid and m is the number of atoms in the biotarget. The number of atoms is approximately equal between different biotarget; is negligibly small compared with the number of cells in the grid and is unknown at the balancing stage. Hence only the number of cells is used in load balancing. Grids are dispatched in such way that a new grid is assigned to GPU with the lowest load according to the number of calculations that have been assigned to GPU.
GPU is a se parate computational unit and it is necessary to provide significant load for each GPU in order to hide latency during memory exchanging. Two critical procedures in the workflow which significantly inhibit computing on GPU are reading biotargets and ligands from the disk and writing completed grids back to the disk. In order to overcome this problem and support an adequate level of load for GPU, the workflow for a single GPU is divided into three central processing unit (CPU) threads: i_thread (for input), o_thread (for output), d_thread (for calculation on GPU). All three threads share a
Fig. 3. Decomposition of the calculation of the single grid
Fig. 4. Decomposition between multiple GPUs
Fig. 5. Runtime manager
targetAtomCount
X Y Z charges
Fig. 6. The organization of information on biological target in GPU memory
special program object called a runtime manager that controls the workflow of the calculation, using of memory and errors. Moreover the runtime manager contains two queues (i_queues and o_queues) for the task for GPU (Fig. 5). There are three types of tasks (Appendix A, B): vdw (the van der Waals task), elec (electrostatic task) and elecDd (electrostatic task that uses the distance dependent approach for calculation of the permittivity). Queue for a single GPU is input of i_thread that goes through all biotargets and grids. i_thread parses biotarget, repacks it to format that is suitable for GPU, forms the runtime representations of the biotarget and puts
it to a set of the runtime biotargets in the runtime manager. Atomic coordinates, charges and vdw types are necessary for the grid calculation from the biotarget. This information is repacked to one dimensional array (Fig. 6). Such organization of memory for biotarget guarantees that all GPUs threads along warps will read the exact same cell of memory hence memory requests will be coalesced.
i_thread forms the runtime representation for each new grid (independent from biotarget) and puts it to a set of runtime grids. For each ligand that is assigned to some grid i_thread runs antechamber program in order to assign 9 -
proper atom types according to GAFF. After that i_thread a adds task to i_queue according to available memory and set of atom types that are presented in ligands. The grid is calculated only for one atom type if some atom types that are presented in ligand have similar vand der Waals parameters. It is allow to reduce the calculation and at the same time save thetg flexibility of customization of the force field. If there is a low level of free memory, i_thread divides set of atom types and forms several vdw tasks. If there is no memory for a new task, i_thread waits until o_thread unloads grids to the disk. The runtime manager has a special watchdog counter to control waiting time and stops calculations if i_thread wait memory is too long. Each biotargets or grids have their own references counter which is incremented by i_thread when it adds a new task that uses this biotarget or grid. i_thread checks all references counters after each new biotarget and remove unused biotargets and grids. It is allowed to use memory more rationally and protect the system against memory leaks when the screening of the large number of biotargets/grids is performed.
d_thread gets a new task from i_ queue, loads to the GPU memory runtime biotarget representation and the runtime grid representation if they have not been already loaded. After that d_thread allocates memory on GPU for grids and starts calculation according to the task type. Then d_thread dumps back the grid to CPU memory and transfers the completed task to o_queue. All steps are
perform synchronously. GPU has asynchronous capabilities however they require using of CPU page-locked memory for asynchronous memory exchanging and it is not rational especially at large sets of input data and when computers with multiple GPUs are used.
o_thread gets the completed task from o_ queue and dumps the completed grids to disk. After that the task is removed, all used memory is freed and references counters are decremented.
If a computer has multiple GPUs, a separate runtime manager is created for each GPU. Such separation allows to use computational resources more effectively especially on the multicore system.
Results and Discussion
All tests were performed on different modern CUDA GPUs with different computer capabilities (2.0, 2.1, 3.5) and different target markets (low-cost and HPC solutions) in order to study the behavior of algorithms on different platforms. GPUs which were used in the test are presented in Table 1.
As mentioned above two different approaches for the calculation of the permittivity were used in this work. A user can select the necessary approach depending on the required priorities (performance or accuracy). Performance tests are presented in Table 2. In general, the usual approach is faster than the distance dependent approach by 1.75-2.37 times.
The results of speedup of algorithm for GPU are presented in Table 3. The base value
Table 1. Test GPUs
GPU Computer capabilities Multiprocessors ALU Market
Tesla M2090 2.0 16 512 HPC
Tesla K20 3.5 13 2496 HPC
GeForce GT 440 2.1 2 96 Low-cost
for comparison is the result of the calculation of 9 grids (size along all dimensions is 64) for one biotarget with using the program AutoGrid4 that was developed in Scripps Research Institute and is used for grids calculation for the program AutoDock4 (Morris et al., 1997; Morris et al., 2009). The tests were performed on the computer with Intel Core i7 920 and 3 GB RAM. Speedup varies on different GPUs but even on a low-cost GPU with the low number of ALUs it is significant.
The results of speedup of implementation with the runtime manager and with different threads for input, output and execution (Fig. 6) are presented in Table 4. The tests were performed by using two Tesla M2090.
They included three cases with 60 grids with different sizes and different ligands for each grid. This conception gives additional speedup regardless of grids size and hides latency of memory exchange.
Additional tests in order to estimate quality of load balancing were performed. Two arrays of GPU were used: 2 GPU Tesla M2090 and 4 GPU Tesla K20. It is a common configuration of arrays of GPU. The average time of execution of task on each GPU and unloading completed grid to the disk for a pair of Tesla M2090 are presented in Table 5.
Similar tests were performed for a quartet of Tesla K20. The results are presented in Table 6. Load is distributed well across multiple GPUs
Table 2. The average time of the kernel with (dd column) and without (not dd column) using the distance dependent approach
GPU not dd,ms dd,ms Speedup (dd/not dd)
Tesla M2090 126.15 220.44 1.75
Tesla K20 87.25 205.82 2.36
GeForce GT 440 740.295 1758.09 2.37
Table 3. Average time of calculation of 9 grids using different GPUs
GPU Elapsed,ms Speedup
AutoGrid 4 74010 1
Tesla M2090 1824.04 40.58
Tesla K20 1523.21 48.59
GeForce GT 440 11370.01 6.51
Table 4. Results of comparison between implementation using single thread and implementation using separate threads (i_o_d column)
Test case single thread,s i_o_d,s speedup
64*64*64 221 145 1.52
128*128*128 1296 877 1.48
Varying size 32-128 702 334 2.11
Table 5. Execution time (d_thread) and dumping time (o_thread) on 2 Tesla M2090
Test case d_thread,s o_thread,s
GPU #0 GPU #1 GPU #0 GPU #1
64*64*64 124 128 114 117
128*128*128 761 754 620 585
Varying size 32-128 235 237 290 291
Table 6. Execution time (d_thread) and dumping time (o_thread) on 4 Tesla K20
Test case d_thread,s o_thread,s
GPU #0 GPU #1 GPU #2 GPU #3 GPU #0 GPU #1 GPU #2 GPU #3
64*64*64 41 43 45 46 69 73 74 76
128*128*128 264 256 267 255 459 421 470 442
Varying size 32-128 96 86 105 95 165 136 163 159
independent from size of array without idle of GPU.
The set of test results shows that the proposed algorithms are computationally effective. They use maximum of computer and GPU resources and scale for different platforms well. The algorithms are implemented in a program for very fast calculation of the large number of grids of force fields GPU-CGFF.
The program is registered in the Federal Institute of Industrial Property of Russian Federation on November 14, 2013. Registration number is 2013660687.
Conclusion
Proposed approach for force field grids calculation demonstrates high performance compared with traditional CPU approaches.
References
Algorithm efficiently and automatically scales computational load on multiple graphics processors. Commonly used force field and accurate distance dependent approach for evaluation of the permittivity are used. The algorithms are useful for acceleration of the ligand-protein molecular docking.
Acknowledgment
The author thanks Sergey Feranchuk from United Institute of Informatics Problems of the National Academy of Sciences of Belarus for helpful consultations during this work; The HPC Research Department of Siberian Federal University and The Tauber Bioinformatics Research Center at University of Haifa for providing of computing resources that were used to carry out the research.
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Appendix A. CUDA kernel for van der Waals calculation
_global_void vdwMultipleKernel(float *deviceTargetInfo,float *deviceRadius,float
*deviceEpsilon,float *deviceProbE,float *deviceProbR,unsigned short int *deviceProbCount,unsigned char *deviceTypes,unsigned int *deviceProteinAtomCount,float
*deviceVdwGrid,float *deviceGridParameters,unsigned short int *deviceGridSize) {
unsigned short int registerProbCount=*deviceProbCount, xIndex,yIndex,zIndex; unsigned int registerProteinAtomCount=*deviceProteinAtomCount,
numberOfCellInGrid=deviceGridSize[0]*deviceGridSize[1]*deviceGridSize[2]; float currentX,currentY,currentZ, r,e,r0; //Loop over all cells
for(unsigned int index=blockIdx.x*blockDim.x+threadIdx.x; index<numberOfCellInGrid; index+=gridDim.x*blockDim.x){
for(unsigned short int probIndex=0;probIndex<registerProbCount;++probIndex) deviceVdwGrid[numberOfCellInGrid*probIndex+index]=0;
xIndex=index/(deviceGridSize[1]*deviceGridSize[2]);
yIndex=(index%(deviceGridSize[1]*deviceGridSize[2]))/deviceGridSize[2];
zIndex=index%deviceGridSize[2];
currentX=xIndex*deviceGridParameters [3]+deviceGridParameters [0]; currentY=yIndex*deviceGridParameters [3]+deviceGridParameters[1]; currentZ=zIndex*deviceGridParameters[3]+deviceGridParameters[2];
//Loop over target atoms
for(unsigned int atomsIndex=0; atomsIndex<registerProteinAtomCount;++atomsIndex){
r=_fsqrt_rn((deviceTargetInfo[atomsIndex]-currentX)*
(deviceTargetInfo[atomsIndex]-currentX)+
(deviceTargetInfo[atomsIndex+registerProteinAtomCount] - currentY)* (deviceTargetInfo[atomsIndex+registerProteinAtomCount]-currentY)+ (deviceTargetInfo[atomsIndex+registerProteinAtomCount*2] -currentZ)* (deviceTargetInfo[atomsIndex+registerProteinAtomCount*2]-currentZ)); //Loop over probes
for(unsigned short int probIndex=0;probIndex<registerProbCount;++probIndex){ r0=deviceProbR[probIndex]+deviceRadius[deviceTypes[atom sIndex]];
e=_fsqrt_rn(deviceProbE[probIndex]*deviceEpsilon[deviceTypes[atomsIndex]]);
deviceVdwGrid[numberOfCellInGrid*probIndex+index]+=
e*(_powf((r0/r),12)-2*_powf((r0/r),6))*((unsigned short int)
(deviceTargetInfo[atomsIndex]>=deviceGridParameters[0]&& deviceTargetInfo[atomsIndex]<=
(deviceGridParameters[0] +deviceGridParameters[3]*deviceGridSize[0]))&&
(deviceTargetInfo[atomsIndex+registerProteinAtomCount]>=
deviceGridParameters[1]&&
deviceTargetInfo[atomsIndex+registerProteinAtomCount]<= (deviceGridParameters[1]+deviceGridParameters[3]*deviceGridSize[1]))&& (deviceTargetInfo[atomsIndex+registerProteinAtomCount* 2]>= deviceGridParameters[2]&&
deviceTargetInfo[atomsIndex+registerProteinAtomCount*2]<= (deviceGridParameters[2] +deviceGridParameters [3 ] * deviceGrid Size[2])));
}}}}
Appendix B. CUDA kernel for electrostatic calculation.
_global_void elDdPrototypeKernel(float *deviceTargetInfo,unsigned int
*deviceProteinAtomCount,float *deviceCoulombPrototype,float *deviceGridParameters,unsigned
short int *deviceGridSize,float *devicePermittivity) {
unsigned int registerProteinAtomCount=*deviceProteinAtomCount,
numberOfCellInGrid=deviceGridSize[0]*deviceGridSize[1]*deviceGridSize[2]; unsigned short int inGrid, xIndex,yIndex,zIndex; float coulomb,r,currentX,currentY,currentZ;
for(unsigned int index=blockIdx.x*blockDim.x+threadIdx.x; index<numberOfCellInGrid;index+=gridDim.x*blockDim.x){ xIndex=index/(deviceGridSize[1]*deviceGridSize[2]); yIndex=(index%(deviceGridSize[1]*deviceGridSize[2]))/deviceGridSize[2]; zIndex=index%deviceGridSize[2];
currentX=xIndex*deviceGridParameters[3]+deviceGridParameters[0]; currentY=yIndex*deviceGridParameters[3]+deviceGridParameters[1]; currentZ=zIndex*deviceGridParameters[3]+deviceGridParameters[2];
coulomb=0;
for(unsigned int atomsIndex=0;atomsIndex<registerProteinAtomCount;++atomsIndex){
r=_fsqrt_rn((deviceTargetInfo[atomsIndex]-currentX)*
(deviceTargetInfo[atomsIndex]-currentX)+
(deviceTargetInfo[atomsIndex+registerProteinAtomCount]-currentY)* (deviceTargetInfo[atomsIndex+registerProteinAtomCount]-currentY)+ (deviceTargetInfo[atomsIndex+registerProteinAtomCount*2]-currentZ) * (deviceTargetInfo[atomsIndex+registerProteinAtomCount*2]-currentZ)); inGrid=((unsigned short int) (deviceTargetInfo[atomsIndex]>=deviceGridParameters[0]&& deviceTargetInfo[atomsIndex]<=
(deviceGridParameters[0]+deviceGridParameters[3]*deviceGridSize[0]))&&
(deviceTargetInfo[atomsIndex+registerProteinAtomCount]>=
deviceGridParameters[1]&&
deviceTargetInfo[atomsIndex+registerProteinAtomCount]<= (deviceGridParameters[1]+deviceGridParameters[3]*deviceGridSize[1]))&& (deviceTargetInfo[atomsIndex+registerProteinAtomCount*2]>= deviceGridParameters[2]&&
deviceTargetInfo[atomsIndex+registerProteinAtomCount*2]<= (deviceGridParameters[2]+deviceGridParameters[3]*deviceGridSize[2])));
coulomb+=(deviceTargetInfo[atomsIndex+registerProteinAtomCount*3]/(r*r))* inGrid*(ELEC_DD_A+(*devicePermittivity-ELEC_DD_A)/ (1+ELEC_DD_K*_expf(ELEC_DD_L*(* devicePermittivity-ELEC_DD_A)*r)));
}
deviceCoulombPrototype[index]=coulomb;
}}
