Key Information and References for RAMD and tauRAMD

For a short description of Random Acceleration Molecular Dynamics (RAMD) and the key references for the method, see the RAMD entry in KBbox

For a short description of how to use RAMD to calculate relative residence times with the tauRAMD protocol, as well as the key references for the method, see the tauRAMD entry in KBbox

For tutorials describing the τRAMD process of setting up and running RAMD simulations for estimation of the relative residence time (τ) of a protein-small molecule complex, look at the GROMACS or NAMD tutorials on KBBox

For implementations of RAMD, versions are available for GROMACS, NAMD, AMBER and OpenMM.

In addition, scripts for tauRAMD and MD-IFP (Interaction FingerPrint Analysis of Molecular Dynamics trajectories) are available.

RAMD and its applications (using the implementation in Gromacs) are described in:

  • Sohraby, F. and Nunes-Alves, A. Characterization of the Bottlenecks and Pathways for Inhibitor Dissociation from [NiFe] Hydrogenase Journal of Chemical Information and Modeling 2024 64 (10), 4193-4203. (2024).
  • de Oliveira, M.V.D., da Costa, K.S., Silva, J.R.A., Lameira, J. and Lima, A.H., Role of UDP‐N‐acetylmuramic acid in the regulation of MurA activity revealed by molecular dynamics simulations. Protein Science, 33(4), p.e4969. (2024).
  • Maciel, L.G., Ferraz, M.V., Oliveira, A.A., Lins, R.D., Dos Anjos, J.V., Guido, R.V. and Soares, T.A., Inhibition of 3-Hydroxykynurenine Transaminase from Aedes aegypti and Anopheles gambiae: A mosquito-specific target to combat the transmission of arboviruses. ACS bio & med Chem Au, 3(2), pp.211-222. (2023).
  • Flores-León, C.D., Colorado-Pablo, L.F., Santos-Contreras, M.Á. and Aguayo-Ortiz, R., Determination of nucleoside DOT1L inhibitors’ residence times by τRAMD simulations. Frontiers in Drug Discovery, 2, p.1083198. (2023).
  • Maximova, E., Postnikov, E.B., Lavrova, A.I., Farafonov, V. and Nerukh, D., Protein–ligand dissociation rate constant from all-atom simulation. The Journal of Physical Chemistry Letters, 12(43), pp.10631-10636. (2021).
  • Kokh, D.B. and Wade, R.C., G protein-coupled receptor–ligand dissociation rates and mechanisms from τRAMD simulations. Journal of Chemical Theory and Computation, 17(10), pp.6610-6623. (2021).
  • Kokh DB et. al. A Workflow for Exploring Ligand Dissociation from a Macromolecule: Efficient Random Acceleration Molecular Dynamics Simulation and Interaction Fingerprints Analysis of Ligand Trajectories. J. Chem. Phys. 153, 125102 (2020); or arXiv 2020 arXiv:2006.11066

RAMD and its applications (using the implementation in NAMD) are described in:

  • Tan, S., Wang, J., Gao, P., Xie, G., Zhang, Q., Liu, H. and Yao, X., Unveiling the Selectivity Mechanism of Type-I LRRK2 Inhibitors by Computational Methods: Insights from Binding Thermodynamics and Kinetics Simulation. ACS Chemical Neuroscience, 14(18), pp.3472-3486. (2023).
  • Tang, R., Wang, Z., Xiang, S., Wang, L., Yu, Y., Wang, Q., Deng, Q., Hou, T. and Sun, H., Uncovering the Kinetic Characteristics and Degradation Preference of PROTAC Systems with Advanced Theoretical Analyses. JACS Au, 3(6), pp.1775-1789. (2023).
  • Zhang, Q., Han, J., Zhu, Y., Tan, S. and Liu, H., Binding thermodynamics and dissociation kinetics analysis uncover the key structural motifs of phenoxyphenol derivatives as the direct InhA inhibitors and the hotspot residues of InhA. International Journal of Molecular Sciences, 23(17), p.10102. (2022).
  • Berger, B. T., Amaral, M., Kokh, D. B., Nunes-Alves, A., Musil, D., Heinrich, T., … and Knapp, S. Structure-kinetic relationship reveals the mechanism of selectivity of FAK inhibitors over PYK2. Cell Chemical Biology, 28(5), 686-698. (2021).
  • Nunes-Alves, A., Kokh, D.B. and Wade, R.C., Ligand unbinding mechanisms and kinetics for T4 lysozyme mutants from τRAMD simulations. Current Research in Structural Biology, 3, pp.106-111. (2021).
  • Zhang, Z., Fan, F., Luo, W., Zhao, Y. and Wang, C., Molecular dynamics revealing a detour-forward release mechanism of tacrine: implication for the specific binding characteristics in butyrylcholinesterase. Frontiers in Chemistry, 8, p.730. (2020).
  • Chaudhary, S.K., Iyyappan, Y., Elayappan, M., Jeyakanthan, J. and Sekar, K., Insights into product release dynamics through structural analyses of thymidylate kinase. International journal of biological macromolecules, 123, pp.637-647. (2019).
  • Bruno, A., Barresi, E., Simola,N., Da Pozzo, E., Costa, B., Novellino, E., Da Settimo, F., Martini, C., Taliani, S. and Cosconati, S. Unbinding of Translocator Protein 18 kDa (TSPO) Ligands: From in Vitro Residence Time to in Vivo Efficacy via in Silico Simulations. ACS Chemical Neuroscience 10 (8), 3805-3814. (2019). DOI: 10.1021/acschemneuro.9b00300
  • Kokh DB et. al. Machine Learning Analysis of τRAMD Trajectories to Decipher Molecular Determinants of Drug-Target Residence Times. Front. Mol. Biosci. (2019) DOI: 10.1021/acs.jctc.8b00230
  • Muvva, C., Murugan, N.A., Kumar Choutipalli, V.S. and Subramanian, V., Unraveling the unbinding pathways of products formed in catalytic reactions involved in SIRT1–3: A random acceleration molecular dynamics simulation study. Journal of Chemical Information and Modeling, 59(10), pp.4100-4115. (2019).
  • Kokh DB et. al. Estimation of Drug-Target Residence Times by τ-Random Acceleration Molecular Dynamics Simulations. J. Chem. Theory Comput. 2018, 14, 7, 3859–3869 2018 DOI: 10.1021/acs.jctc.8b00230
  • Wells, G., Yuan, H., McDaniel, M.J., Kusumoto, H., Snyder, J.P., Liotta, D.C. and Traynelis, S.F., The GluN2B‐Glu413Gly NMDA receptor variant arising from a de novo GRIN2B mutation promotes ligand‐unbinding and domain opening. Proteins: Structure, Function, and Bioinformatics, 86(12), pp.1265-1276. (2018).
  • Du, J., Liu, L., Guo, L.Z., Yao, X.J. and Yang, J.M., Molecular basis of P450 OleT JE: an investigation of substrate binding mechanism and major pathways. Journal of Computer-Aided Molecular Design, 31, pp.483-495. (2017).
  • Zhao, Y., She, N., Zhang, X., Wang, C. and Mo, Y., Product release mechanism and the complete enzyme catalysis cycle in yeast cytosine deaminase (yCD): A computational study. Biochimica et Biophysica Acta (BBA)-Proteins and Proteomics, 1865(8), pp.1020-1029. (2017).
  • Pietra, F., On Dioxygen and Substrate Access to Soluble Methane Monooxygenases: An all‐Atom Molecular Dynamics Investigation in Water Solution. Chemistry & Biodiversity, 14(1), p.e1600158. (2017).
  • Niu, Y., Li, S., Pan, D., Liu, H., Yao, X. Computational Study on the Unbinding Pathways of B-RAF Inhibitors and Its Implication for the Difference of Residence Time: Insight from Random Acceleration and Steered Molecular Dynamics Simulations. Phys. Chem. Chem. Phys. 2016, 18 (7),5622–5629, DOI: 10.1039/C5CP06257H
  • Xiaofeng Yu, Prajwal Nandekar, Ghulam Mustafa, Vlad Cojocaru, Galina I. Lepesheva and Rebecca C. Wade. Ligand tunnels in T. brucei and human CYP51: Insights for parasite-specific drug design. Biochim. Biophys. Acta (BBA) – General Subjects, (2016) 1860:67-78, DOI: 10.1016/j.bbagen.2015.10.015
  • Liu, Y., Tu, G., Lai, X., Kuang, B. and Li, S., Exploring ligand dissociation pathways from aminopeptidase N using random acceleration molecular dynamics simulation. Journal of molecular modeling, 22, pp.1-7. (2016).
  • Lopata, A., Leveles, I., Bendes, Á.Á., Viskolcz, B., Vértessy, B.G., Jójárt, B. and Tóth, J., A hidden active site in the potential drug target mycobacterium tuberculosis dUTPase is accessible through small amplitude protein conformational changes. Journal of Biological Chemistry, 291(51), pp.26320-26331. (2016).
  • Chen, N., Zhao, Y., Lu, J., Wu, R. and Cao, Z., Mechanistic insights into the rate-limiting step in purine-specific nucleoside hydrolase. Journal of Chemical Theory and Computation, 11(7), pp.3180-3188. (2016).
  • Cai, J., Li, J., Zhang, J., Ding, S., Liu, G., Li, W. and Tang, Y., Computational insights into inhibitory mechanism of azole compounds against human aromatase. RSC advances, 5(110), pp.90871-90880. (2015).
  • Shang, Y., LeRouzic, V., Schneider, S., Bisignano, P., Pasternak, G.W. and Filizola, M., Mechanistic insights into the allosteric modulation of opioid receptors by sodium ions. Biochemistry, 53(31), pp.5140-5149. (2014).
  • Pietra, F., Binding Pockets and Permeation Channels for Dioxygen through Cofactorless 3‐Hydroxy‐2‐methylquinolin‐4‐one 2, 4‐Dioxygenase in Association with Its Natural Substrate, 3‐Hydroxy‐2‐methylquinolin‐4 (1H)‐one. A Perspective from Molecular Dynamics Simulations. Chemistry & Biodiversity, 11(6), pp.861-871. (2014).
  • Zhuang, S., Bao, L., Linhananta, A. and Liu, W., Molecular modeling revealed that ligand dissociation from thyroid hormone receptors is affected by receptor heterodimerization. Journal of Molecular Graphics and Modelling, 44, pp.155-160. (2013).
  • Pietra, F., On the pathways of biologically relevant diatomic gases through proteins. Dioxygen and heme oxygenase from the perspective of molecular dynamics. Chemistry & Biodiversity, 10(4), pp.556-568. (2013).
  • Mirza, I.A., Burk, D.L., Xiong, B., Iwaki, H., Hasegawa, Y., Grosse, S., Lau, P.C. and Berghuis, A.M., Structural analysis of a novel cyclohexylamine oxidase from Brevibacterium oxydans IH-35A. PloS one, 8(3), p.e60072. (2013).
  • Vlad Cojocaru, Peter J. Winn and Rebecca C. Wade, Multiple, Ligand-dependent Routes from the Active Site of Cytochrome P450 2C9. Curr. Drug. Metab. (2012) 13:143-154, DOI: 10.2174/138920012798918462
  • Merchant, B. A., and Madura, J. D. Insights from molecular dynamics: the binding site of cocaine in the dopamine transporter and permeation pathways of substrates in the leucine and dopamine transporters. Journal of Molecular Graphics and Modelling, 38, 1-12. (2012).
  • Kalyaanamoorthy, S., and Chen, Y. P. P. Exploring inhibitor release pathways in histone deacetylases using random acceleration molecular dynamics simulations. Journal of chemical information and modeling, 52(2), 589-603. (2012).
  • Yu, R., Kaas, Q. and Craik, D.J., Delineation of the unbinding pathway of α-conotoxin ImI from the α7 nicotinic acetylcholine receptor. The Journal of Physical Chemistry B, 116(21), pp.6097-6105. (2012).
  • Pietra, F. Molecular‐Dynamics Simulation of Dioxygen Egress from 12/15‐Lipoxygenase Arachidonic Acid Complex. Chemistry & Biodiversity, 9(6), 1019-1032. (2012).
  • Vashisth, H., Abrams, C.F. Ligand escape pathways and (un)binding free energy calculations for the hexameric insulin-phenol complex. Biophys. J. 95, 4193-4204 (2008). DOI:10.1529/biophysj.108.139675

RAMD and its applications (using the implementation in AMBER unless otherwise specified) are described in

  • Lüdemann SK, Carugo O, Wade RC. Substrate access to cytochrome P450cam: a comparison of a thermal motion pathway analysis with molecular dynamics simulation data. J. Mol. Model. (1997) 3, 369-374. DOI:10.1007/s008940050053 (Initial ARGOS implementation)
  • Luedemann, S.K., Lounnas, V. and R. C. Wade. How do Substrates Enter and Products Exit the Buried Active Site of Cytochrome P450cam ? 1. Random Expulsion Molecular Dynamics Investigation of Ligand Access Channels and Mechanisms. J Mol Biol, 303:797-811 (2000). doi:10.1002/jmbi.2000.4154 (First description of method and implementation in ARGOS)
  • Luedemann, S.K., Gabdoulline,R.R., Lounnas, V. and R. C. Wade. Substrate access to cytochrome P450cam investigated by molecular dynamics simulations: An interactive look at the underlying mechanisms. Internet Journal of Chemistry, 4, 6 (2001). (using the ARGOS implementation)
  • Winn,P., Luedemann, S.K., Gauges,R., Lounnas, V. and R. C. Wade. Comparison of the dynamics of substrate access channels in three cytochrome P450s reveals different opening mechanisms and a new functional role for a buried arginine PNAS, 99, 5361-5366 (2002). Full text (using the ARGOS implementation)
  • Schleinkofer, K., Sudarko, Winn,P., Luedemann, S.K. and R. C. Wade. Do mammalian cytochrome P450s show multiple ligand access pathways and ligand channelling? EMBO Reports, 6, 584-589 (2005). doi:10.1038/sj.embor.7400420
  • Carlsson, P., Burendahl, S., Nilsson, L. Unbinding of retinoic acid from the retinoic acid receptor by random expulsion molecular dynamics. Biophys. J. 91, 3151-3161 (2006).doi:10.1529/biophysj.106.082917 (Implementation in CHARMM)
  • Wang, T., Duan, Y. Chromophore channeling in the G-protein coupled receptor rhodopsin J. Am. Chem. Soc. 129, 6970-6971 (2007).doi:10.1021/ja0691977
  • * Bertoša, B., Kojić-Prodić, B., Wade, R. C., and Tomić, S. Mechanism of auxin interaction with Auxin Binding Protein (ABP1): a molecular dynamics simulation study. Biophysical journal, 94(1), 27-37. (2008).
  • Long, D., Mu, Y. Yang, D. Molecular Dynamics Simulation of Ligand Dissociation from Liver Fatty Acid Binding Protein. PLoS ONE 4, e6801 (2008).doi:10.1371/journal.pone.0006081 (Implementation of a variant of RAMD in GROMACS)
  • Perakyla, M. Ligand unbinding pathways from the vitamin D receptor studied by molecular dynamics simulations. 38, 185-198 (2009).doi:10.1007/s00249-008-0369-x
  • Klvana, M. et al. Pathways and Mechanisms for Product Release in the Engineered Haloalkane Dehalogenases Explored Using Classical and Random Acceleration Molecular Dynamics Simulations J. Mol. Biol. 392, 1339-1356 (2009). doi:10.1016/j.jmb.2009.06.076
  • Pavlova, M. et al. Redesigning dehalogenase access tunnels as a strategy for degrading an anthropogenic substrate Nature Chem. Biol. 5, 727-733 (2009). doi:10.1038/nchembio.205
  • Wang, T., Duan, Y. Ligand entry and exit pathways in the beta2-adrenergic receptor. J. Mol. Biol. 392, 1102-1115 (2009). doi:10.1016/j.jmb.2009.07.093
  • Li, W., Shen, J., Liu, G., Tang, Y., and Hoshino, T. Exploring coumarin egress channels in human cytochrome P450 2A6 by random acceleration and steered molecular dynamics simulations. Proteins: Structure, Function, and Bioinformatics, 79(1), 271-281. (2011).
  • Shen, Z., Cheng, F., Xu, Y., Fu, J., Xiao, W., Shen, J., Liu, G., Li, W. and Tang, Y. Investigation of indazole unbinding pathways in CYP2E1 by molecular dynamics simulations. PloS one, 7(3), e33500. (2012).
  • Li, W., Fu, J., Cheng, F., Zheng, M., Zhang, J., Liu, G., and Tang, Y. Unbinding pathways of GW4064 from human farnesoid X receptor as revealed by molecular dynamics simulations. Journal of chemical information and modeling, 52(11), 3043-3052. (2012).
  • Yu, X., Cojocaru, V. and Wade, R.C.,. Conformational diversity and ligand tunnels of mammalian cytochrome P 450s. Biotechnology and applied biochemistry, 60(1), pp.134-145. (2013).
  • Cai, J., Li, J., Zhang, J., Ding, S., Liu, G., Li, W. and Tang, Y., Computational insights into inhibitory mechanism of azole compounds against human aromatase. RSC advances, 5(110), pp.90871-90880. (2015).