Flexible Residues and Ligand Coordinates Located Far Away from Rigid Receptor Coordinates

[ctrolinder]

Hello, I have been attempting to dock a ligand library using:

/home/username/Desktop/DSDPFlex_Clone/DSDPFlex/bin/DSDPflex \ --ligand_batch /home/username/Desktop/DSDPFlex_KynLib/KynLib_Gypsum_Ligands/pdbqt_config_text/pdbqt_out_batch_1.txt \ --protein /home/username/Desktop/DSDPFlex_KynLib/Receptor/4kcd_rigid.pdbqt \ --flex /home/username/Desktop/DSDPFlex_KynLib/Receptor/4kcd_flex.pdbqt \ --box_min -0.025 -15.2875 -21.800 \ --box_max 11.225 6.0875 -6.800 \ --ligbox_min -7.943 -6.165 -6.628 \ --ligbox_max 7.085 4.478 7.779 \ --exhaustiveness 384 \ --search_depth 40 \ --top_n 1 \ --log /home/username/Desktop/DSDPFlex_KynLib/Output/Output_log/DSDP_out_batch_1.log

This executes DSDPFlex without any warnings, however, looking at the output files, my flexible receptor coordinates and ligand coordinates after docking are located far from the rigid receptor coordinates. I would greatly appreciate any feedback as to why this may be happening and if there is a way to fix this issue. Here are some abbreviated examples with the rigid and flex Input files first followed by the Output flex and ligand files:

Inputs --

Rigid: ATOM 1 N ASN A 3 -5.631 -10.613 -46.747 1.00 63.07 0.615 N ATOM 2 CA ASN A 3 -4.248 -10.142 -46.747 1.00 62.58 0.408 C ATOM 3 C ASN A 3 -3.885 -9.403 -45.460 1.00 50.69 0.258 C ATOM 4 O ASN A 3 -2.900 -9.745 -44.800 1.00 57.66 -0.271 OA ATOM 5 CB ASN A 3 -3.988 -9.243 -47.962 1.00 68.57 0.153 C ATOM 6 CG ASN A 3 -2.629 -8.554 -47.905 1.00 72.27 0.218 C ATOM 7 OD1 ASN A 3 -2.542 -7.325 -47.949 1.00 76.13 -0.274 OA ATOM 8 ND2 ASN A 3 -1.564 -9.344 -47.797 1.00 67.55 -0.370 N ATOM 9 1HD2 ASN A 3 -1.663 -10.198 -47.763 1.00 81.03 0.159 HD ATOM 10 2HD2 ASN A 3 -0.776 -9.001 -47.761 1.00 81.03 0.159 HD

Flex: BEGIN_RES TYR A 97 REMARK 3 active torsions: REMARK status: ('A' for Active; 'I' for Inactive) REMARK 1 A between atoms: CA and CB
REMARK 2 A between atoms: CB and CG
REMARK 3 A between atoms: CZ and OH
ROOT ATOM 1 CA TYR A 97 0.088 -6.677 -15.445 1.00 8.56 0.180 C ENDROOT BRANCH 1 2 ATOM 2 CB TYR A 97 1.576 -6.456 -15.183 1.00 10.37 0.073 C BRANCH 2 3 ATOM 3 CG TYR A 97 2.043 -5.039 -15.463 1.00 8.72 -0.056 A ATOM 4 CD2 TYR A 97 2.121 -4.101 -14.440 1.00 8.38 0.010 A ATOM 5 CE2 TYR A 97 2.541 -2.795 -14.697 1.00 10.62 0.037 A ATOM 6 CZ TYR A 97 2.899 -2.439 -15.988 1.00 9.41 0.065 A ATOM 7 CE1 TYR A 97 2.837 -3.362 -17.018 1.00 10.53 0.037 A ATOM 8 CD1 TYR A 97 2.410 -4.641 -16.756 1.00 10.66 0.010 A BRANCH 6 9 ATOM 9 OH TYR A 97 3.364 -1.173 -16.317 1.00 11.48 -0.361 OA ATOM 10 HH TYR A 97 4.036 -0.999 -15.881 1.00 13.74 0.217 HD ENDBRANCH 6 9 ENDBRANCH 2 3 ENDBRANCH 1 2 END_RES TYR A 97

Outputs --

Flex: MODEL 0 REMARK DSDP RESULT: -0.894304 BEGIN_RES TYR A 97 REMARK 3 active torsions: REMARK status: ('A' for Active; 'I' for Inactive) REMARK 1 A between atoms: CA and CB
REMARK 2 A between atoms: CB and CG
REMARK 3 A between atoms: CZ and OH
ROOT ATOM 1 CA TYR A 97 -57.745 -60.114 -93.407 1.00 8.56 0.180 C ENDROOT BRANCH 1 2 ATOM 2 CB TYR A 97 -56.257 -59.893 -93.145 1.00 10.37 0.073 C BRANCH 2 3 ATOM 3 CG TYR A 97 -55.790 -58.476 -93.425 1.00 8.72 -0.056 A ATOM 4 CD2 TYR A 97 -55.712 -57.538 -92.402 1.00 8.38 0.010 A ATOM 5 CE2 TYR A 97 -55.292 -56.232 -92.659 1.00 10.62 0.037 A ATOM 6 CZ TYR A 97 -54.934 -55.876 -93.950 1.00 9.41 0.065 A ATOM 7 CE1 TYR A 97 -54.996 -56.799 -94.980 1.00 10.53 0.037 A ATOM 8 CD1 TYR A 97 -55.423 -58.078 -94.718 1.00 10.66 0.010 A BRANCH 6 9 ATOM 9 OH TYR A 97 -54.469 -54.610 -94.279 1.00 11.48 -0.361 OA ATOM 10 HH TYR A 97 -53.797 -54.436 -93.843 1.00 13.74 0.217 HD ENDBRANCH 6 9 ENDBRANCH 2 3 ENDBRANCH 1 2 END_RES TYR A 97

Ligand: MODEL 0 REMARK DSDP RESULT: -0.894304 REMARK 3 active torsions: REMARK status: ('A' for Active; 'I' for Inactive) REMARK 1 A between atoms: C4_4 and C5_5 REMARK 2 A between atoms: C7_10 and N2_11 REMARK 3 A between atoms: C12_18 and O5_19 ROOT HETATM 1 C1 UNL 1 -55.017 -54.195 -80.420 1.00 0.00 0.018 C HETATM 2 C2 UNL 1 -55.962 -54.156 -79.672 1.00 0.00 -0.072 C HETATM 3 C3 UNL 1 -57.103 -54.103 -78.783 1.00 0.00 0.086 A HETATM 4 C4 UNL 1 -57.036 -54.579 -77.453 1.00 0.00 0.155 A HETATM 5 N1 UNL 1 -58.141 -54.495 -76.669 1.00 0.00 -0.237 NA HETATM 6 C6 UNL 1 -59.323 -53.975 -77.088 1.00 0.00 0.103 A HETATM 7 C7 UNL 1 -60.430 -53.932 -76.205 1.00 0.00 0.132 A HETATM 8 C8 UNL 1 -61.653 -53.425 -76.674 1.00 0.00 0.038 A HETATM 9 C9 UNL 1 -61.776 -52.959 -77.980 1.00 0.00 0.003 A HETATM 10 C10 UNL 1 -60.686 -52.990 -78.847 1.00 0.00 0.017 A HETATM 11 C11 UNL 1 -59.443 -53.498 -78.419 1.00 0.00 0.030 A HETATM 12 C12 UNL 1 -58.308 -53.561 -79.267 1.00 0.00 0.099 A ENDROOT BRANCH 4 13 HETATM 13 C5 UNL 1 -55.820 -55.172 -76.845 1.00 0.00 0.230 C HETATM 14 O1 UNL 1 -54.748 -55.300 -77.492 1.00 0.00 -0.643 OA HETATM 15 O2 UNL 1 -55.859 -55.602 -75.524 1.00 0.00 -0.643 OA ENDBRANCH 4 13 BRANCH 12 16 HETATM 16 O5 UNL 1 -58.330 -53.098 -80.590 1.00 0.00 -0.358 OA HETATM 17 H5 UNL 1 -59.125 -52.670 -81.041 1.00 0.00 0.217 HD ENDBRANCH 12 16 BRANCH 7 18 HETATM 18 N2 UNL 1 -60.331 -54.398 -74.841 1.00 0.00 -0.113 N HETATM 19 O3 UNL 1 -61.364 -54.643 -74.183 1.00 0.00 -0.532 OA HETATM 20 O4 UNL 1 -59.112 -54.507 -74.212 1.00 0.00 -0.532 OA ENDBRANCH 7 18 TORSDOF 3 ENDMDL

[PKUGaoGroup]

The cuda may be not well compiled. Please try to re-compile DSDPFlex. Before compiling, change "sm_70" to "sm_60" in ./DSDPFlex_v0.2/Makefile. If this issue is not been solved, please tell me.

[ctrolinder]

I attempted to re-compile with that change to Makefile and it appears that I am still having the same issue. Let me know if you need any further information from my end. Thanks!

[PKUGaoGroup]

I found that there are some problems of the setting of boxsize in your running script. The x, y, and z of ligbox_min should not be smaller than that of box_min, and the x, y, and z of ligbox_max should not be larger than that of box_max. It means that the box should cover the ligand box in x, y, and z axis. Please change the setting of boxsize. If the issue is not been solved, please provide all input files (pdbqt files of ligand, rigid_part, and flex_part of proteins) to us using a zip file.

[ctrolinder]

Thank you for the quick response. I have made previous attempts at docking without including the ligbox as well and have found that I still encounter the same issues. Perhaps there is something wrong with my preparation of the rigid/flexible pdbqt files. I have used both AutoDock Tools GUI and scripts for preparing the receptor, but either method results in the same docking outputs. I have attached a zip file containing both the input files and output results from docking. I appreciate any input you can give me. Thanks! 4kcd_flexdocking.zip

[PKUGaoGroup]

I used your inputs to run the flexible docking, and the running script is : ./DSDPflex --ligand compound.pdbqt --protein receptor_rigid.pdbqt --flex receptor_flex.pdbqt --box_min 28 -30 -36 --box_max 48 -7 -11 there is no problems in the output files, please see the attachment. results.zip

There is no problems of the input pdbqt files. I think the problem happens when the CUDA was not well compiled in DSDPFlex. Please clean all compiled files in DSDPFlex_v0.2 using "make clean" command, and check your computer CUDA version, and change the sm_70 to a suitable one to re-compile DSDPFlex.

[ctrolinder]

Thanks for all of your assistance with this! It looks like my original CUDA install when I first tried to compile was problematic. I thought there was still an issue with CUDA even after uninstalling and reinstalling, but after some troubleshooting and finding that my system was able to successfully compile NVIDIA cuda-samples, I decided to clone the repository again and compile DSDPFlex from scratch. Changed my Makefile sm_70 to sm_86 for my gpu (3090 ti) and was able to successfully run my simulations. Everything looks good now. Thanks again!