Method development

On-the-Fly Learning and Sampling of Ligand Binding by High-Throughput Molecular Simulations

WU tags: BenAdapt

Description

Experiment image

The most important information that can be taken out of a protein-ligand binding simulation is the binding poses of the ligand, the binding pathways and the free energy of binding. However in classical sampling simulations lots of simulation time is wasted re-sampling areas of low interest which might not lie on the binding pathway or have already been sampled adequately. Therefore, we proposed a adaptive sampling method by which it is possible to sample more strongly along the binding pathway of a ligand and thus achieved a 10 times speedup on the estimation of the binding free energy of the ligand compared to classical sampling.

Publications

  • S. Doerr and G. De Fabritiis, On-the-Fly Learning and Sampling of Ligand Binding by High-Throughput Molecular Simulations, J. Chem. Theory Comput., 10 (5), 2064-2069, (2014)

BadgeRankNameCredit
wat1 Stoneageman17,694,500.00
wat2 RaymondFO*9,307,400.00
wat3 Firehawk8,786,400.00
wat4 Retvari Zoltan*6,772,200.00
wat5 flashawk6,071,100.00
wat6 HA-SOFT, s.r.o.5,639,400.00
wat7 Venec5,520,600.00
wat8 Rick A. Sponholz5,366,400.00
wat9 dominik4,821,000.00
wat10 For the Universe ( Apaszko-Kaszkiety )4,597,400.00
Number of contributors: 1283

Kinetic Characterization of Fragment Binding in AmpC beta-Lactamase by High-Throughput Molecular Simulations

WU tags: 2HDQ

Description

Experiment image

Small molecules used in fragment-based drug discovery form multiple, promiscuous binding complexes difficult to capture experimentally. Here, we identify such binding poses and their associated energetics and kinetics using molecular dynamics simulations on AmpC β-lactamase. Only one of the crystallographic binding poses was found to be thermodynamically favorable; however, the ligand shows several binding poses within the pocket. This study demonstrates free-binding molecular simulations in the context of fragment-to-lead development and its potential application in drug design.

Publications

  • P. Bisignano*, S. Doerr*, M. J. Harvey, A. D. Favia, A. Cavalli, and G. De Fabritiis, Kinetic Characterization of Fragment Binding in AmpC beta-Lactamase by High-Throughput Molecular Simulations, J. Chem. Info. Model., 54 (2), 362-366, 2014

BadgeRankNameCredit
wat1 Stoneageman24,067,500.00
wat2 Firehawk14,355,000.00
wat3 Retvari Zoltan*12,825,000.00
wat4 RaymondFO*12,420,000.00
wat5 flashawk12,220,000.00
wat6 Venec11,376,875.00
wat7 Bedrich Hajek8,505,000.00
wat8 For the Universe ( Apaszko-Kaszkiety )8,077,500.00
wat9 underwater8,055,000.00
wat10 werdwerdus6,401,250.00
Number of contributors: 2163

Free binding of inhibitor benzamidine to enzyme trypsin

WU tags: TRYP, PYRT

Description

Identification of inhibitor molecules (drugs) that bind to enzymes or other proteins (targets) has been, and will be, the principal goal in drug discovery processes. Computational biologists/biochemists develop computational methods that span from ligand binding pose prediction to ligand binding affinity calculations, to aid in the quest for finding new, better and safer drugs. With our experiments, we show for the first time, a complete process of binding of a drug-like molecule to its target protein. Our molecules are used as a toy model in a proof-of-concept study for future and more relevant cases. In addition to reproduction of crystallographic ligand binding pose (also tackled by much cheaper but more coarse-grained techniques named 'computational docking'), we show the complete pathway of binding that the inhibitor follows from the solvent to the pocket where it binds. We detect several amino-acids in trypsin that consistently interact with benzamidine as it binds, which indicates that there is a prefered pathway for benzamidine to bind and therefore inhibit the function of trypsin. The principal outcome of this work is that with Molecular Dynamics simulations, it is now possible to study full binding events, being able to visualize and quantify the whole process of binding with a single computational experiment. We are confident that this achievement will allow a much deeper understanding of the processes of binding for small drug-like molecules which may then lead to the design of new, better and safer drugs.

Publications

  • I. Buch, T. Giorgino and G. De Fabritiis, Complete reconstruction of an enzyme-inhibitor binding process by molecular dynamics simulations, Proc. Natl. Acad. Sci. USA 108(25), 10184-10189 (2011)

BadgeRankNameCredit
wat1 Stoneageman15,732,027.00
wat2 Retvari Zoltan*5,832,012.00
wat3 escape5,443,161.00
wat4 whizbang4,093,559.00
wat5 tng*3,846,724.00
wat6 Bikermatt3,768,642.00
wat7 dataman3,575,314.00
wat8 netwraith3,510,954.00
wat9 comfortw3,481,642.00
wat10 dak16403,236,762.00
Number of contributors: 4410

Molecular simulations of the SH2 and ligand peptide binding affinity

WU tags: pYEEI, SH2

Description

The SH2 is a protein domain involved in protein-protein interactions. This particular domain plays a major role in cell communication on the sigalling processes for cell growth and development. However, the end goal for running such simulations is not to expand the knowldege on this particular system, but to use it as a model for developing methods to calculate protein-protein binding affinities.
Such methods will be very useful, for example, in the study of why certain wrong forms of proteins stop interacting with other partner proteins, as a way to give explanation to diseases in which these sort of mechanisms occur.

Publications

  • I. Buch, S. K. Sadiq and G. De Fabritiis, Optimized potential of mean force calculations of standard binding free energy, J. Chem. Theory Comput., 7, 1765–1772 (2011)
  • I. Buch, M. J. Harvey, T. Giorgino, D. P. Anderson and G. De Fabritiis, High-throughput all-atom molecular dynamics simulations using distributed computing, J. Chem. Inf. and Mod. 50, 397 (2010)

BadgeRankNameCredit
wat1 Stoneageman76,590,546.00
wat2 dak164036,161,500.00
wat3 For the Universe ( Apaszko-Kaszkiety )31,711,633.00
wat4 whizbang25,439,249.00
wat5 comfortw21,920,469.00
wat6 123bob20,694,903.00
wat7 tng*20,332,716.00
wat8 dajeepster20,182,204.00
wat9 CNT - IQE19,654,731.00
wat10 Oleg Tchij18,806,232.00
Number of contributors: 9662

Forward-Reverse Steered Molecular Dynamics

WU tags: GA

Description

Potassium ion permeation in Gramicidin A. We are giving workunits comprising full-atom simulations of gramidicin A for ion transport, a total of 30,000 atoms. Each workunit lasts less than one day and you have to complete it before 4 days.

Publications

  • T. Giorgino and G. De Fabritiis, A high-throughput steered molecular dynamics study on the free energy profile of ion permeation through gramicidin A, J. Chem. Theory Comput.,7 , 1943–1950 (2011)

BadgeRankNameCredit
wat1 Stoneageman4,713,395.00
wat2 dak16403,857,211.00
wat3 GPUGRID Role account3,350,192.00
wat4 Oleg Tchij3,212,435.00
wat5 For the Universe ( Apaszko-Kaszkiety )3,163,300.00
wat6 CNT - IQE2,107,085.00
wat7 123bob1,990,814.00
wat8 X-Files 271,609,954.00
wat9 kevint1,506,964.00
wat10 netwraith1,353,994.00
Number of contributors: 2450