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Attention-based generative models for de novo molecular design

Orion Dollar, Nisarg Joshi, David Beck, Jim Pfaendtner
2021 Chemical Science  
Attention mechanisms have led to many breakthroughs in sequential data modeling but have yet to be incorporated into any generative algorithms for molecular design. Here we explore the impact of...
doi:10.1039/d1sc01050f fatcat:7epm2vtmxja2hj4k3lmnd3aste

Comparison of Three Ionic Liquid-Tolerant Cellulases by Molecular Dynamics

Vance Jaeger, Patrick Burney, Jim Pfaendtner
2015 Biophysical Journal  
We have employed molecular dynamics to investigate the differences in ionic liquid tolerance among three distinct family 5 cellulases from Trichoderma viride, Thermogata maritima, and Pyrococcus horikoshii. Simulations of the three cellulases were conducted at a range of temperatures in various binary mixtures of the ionic liquid 1-ethyl-3-methyl-imidazolium acetate with water. Our analysis demonstrates that the effects of ionic liquids on the enzymes vary in each individual case from local
more » ... ctural disturbances to loss of much of one of the enzyme's secondary structure. Enzymes with more negatively charged surfaces tend to resist destabilization by ionic liquids. Specific and unique structural changes in the enzymes are induced by the presence of ionic liquids. Disruption of the secondary structure, changes in dynamical motion, and local changes in the binding pocket are observed in less tolerant enzymes. Ionic-liquid-induced denaturation of one of the enzymes is indicated over the 500 ns timescale. In contrast, the most tolerant cellulase behaves similarly in water and in ionic-liquid-containing mixtures. Unlike the heuristic approaches that attempt to predict enzyme stability using macroscopic properties, molecular dynamics allows us to predict specific atomic-level structural and dynamical changes in an enzyme's behavior induced by ionic liquids and other mixed solvents. Using these insights, we propose specific experimentally testable hypotheses regarding the origin of activity loss for each of the systems investigated in this study.
doi:10.1016/j.bpj.2014.12.043 pmid:25692593 pmcid:PMC4336362 fatcat:omao3dukprb6zgzz34ppctbvey

IL-Net: Using Expert Knowledge to Guide the Design of Furcated Neural Networks [article]

Khushmeen Sakloth, Wesley Beckner, Jim Pfaendtner, Garrett B. Goh
2018 arXiv   pre-print
Deep neural networks (DNN) excel at extracting patterns. Through representation learning and automated feature engineering on large datasets, such models have been highly successful in computer vision and natural language applications. Designing optimal network architectures from a principled or rational approach however has been less than successful, with the best successful approaches utilizing an additional machine learning algorithm to tune the network hyperparameters. However, in many
more » ... ical fields, there exist established domain knowledge and understanding about the subject matter. In this work, we develop a novel furcated neural network architecture that utilizes domain knowledge as high-level design principles of the network. We demonstrate proof-of-concept by developing IL-Net, a furcated network for predicting the properties of ionic liquids, which is a class of complex multi-chemicals entities. Compared to existing state-of-the-art approaches, we show that furcated networks can improve model accuracy by approximately 20-35%, without using additional labeled data. Lastly, we distill two key design principles for furcated networks that can be adapted to other domains.
arXiv:1809.05127v1 fatcat:uawtdzef2zekfipkoghc5kh45u

Systematic Multiscale Parameterization of Heterogeneous Elastic Network Models of Proteins

Edward Lyman, Jim Pfaendtner, Gregory A. Voth
2008 Biophysical Journal  
We present a method to parameterize heterogeneous elastic network models (heteroENMs) of proteins to reproduce the fluctuations observed in atomistic simulations. Because it is based on atomistic simulation, our method allows the development of elastic coarse-grained models of proteins under different conditions or in different environments. The method is simple and applicable to models at any level of coarse-graining. We validated the method in three systems. First, we computed the persistence
more » ... length of ADP-bound F-actin, using a heteroENM model. The value of 6.1 6 1.6 mm is consistent with the experimentally measured value of 9.0 6 0.5 mm. We then compared our method to a uniform elastic network model and a realistic extension algorithm via covariance Hessian (REACH) model of carboxy myoglobin, and found that the heteroENM method more accurately predicted mean-square fluctuations of a-carbon atoms. Finally, we showed that the method captures critical differences in effective harmonic interactions for coarse-grained models of the N-terminal Bin/amphiphysin/Rvs (N-BAR) domain of amphiphysin, by building models of N-BAR both bound to a membrane and free in solution.
doi:10.1529/biophysj.108.139733 pmid:18658214 pmcid:PMC2567941 fatcat:xf4q6u5honaarl4nwth3xkeakq

Studying the Effects of Methionine Oxidation on Human Fibrin with Multiscale Simulations

Patrick R. Burney, Jim Pfaendtner
2014 Biophysical Journal  
Burney, Jim Pfaendtner. Chemical Engineering, University of Washington, Seattle, WA, USA.  ... 
doi:10.1016/j.bpj.2013.11.3367 fatcat:3hga6t5ss5fgbl6eohlcdzrgsu

Structure and Dynamics of the Actin Filament

Jim Pfaendtner, Edward Lyman, Thomas D. Pollard, Gregory A. Voth
2010 Journal of Molecular Biology  
We used all-atom molecular dynamics simulations to investigate the structure and properties of the actin filament, starting with either the recent Oda model or the older Holmes model. Simulations of monomeric and polymerized actin show that polymerization changes the nucleotide-binding cleft, bringing together the Q137 side chain and bound ATP in a way that may enhance ATP hydrolysis rate in the filament. Simulations with different bound nucleotides and conformations of the DNase I binding loop
more » ... show that the persistence length of the filament depends only on the loop conformation. The computational modeling reveals how bound phalloidin stiffens actin filaments and inhibits the release of the γ-phosphate from ADP-P i actin.
doi:10.1016/j.jmb.2009.11.034 pmid:19931282 pmcid:PMC2815099 fatcat:e7mrzwiqvjgx3nn72i37yxuzny

Elucidating the molecular interactions between uremic toxins and the Sudlow II binding site of human serum albumin [article]

Josh Smith, Jim Pfaendtner
2020 bioRxiv   pre-print
Protein bound uremic toxins (PBUTs) are known to bind strongly with the primary drug carrying sites of human serum albumin (HSA), Sudlow site I and Sudlow site II. A detailed energetic and structural description of PBUT interactions with these binding sites would provide useful insight into the design of materials that specifically displace and capture PBUTs. In this work, we used molecular dynamics (MD) simulations to study in atomistic detail 4 PBUTs bound in Sudlow site II. Specifically, we
more » ... sed the experimentally resolved X-ray structure of simulated indoxyl sulfate (IS) bound to Sudlow site II (PBD ID: 2BXH) to generate initial binding poses for p-cresyl sulfate (pCS), indole-3-acetic acid (IAA), and hippuric acid (HA). We calculated the interaction energy between toxin and protein in MD simulations and performed mean shift clustering on the collection of molecular structures from MD to identify the primary binding modes of each toxin. We find that all 4 toxins are primarily stabilized by electrostatic interactions between their anionic moiety and the hydrophilic residues in Sudlow site II. We observed transience in the strongest toxin-protein interaction, a charge-pairing with the positively charged R410 residue. We confirm the finding that the primary binding pose of IS in Sudlow site II is stabilized by a hydrogen bond with the carbonyl oxygen of L430, and find that this is also true for IAA. We provide insight into the chemical functional groups that might be incorporated to improve the specificity of synthetic materials for PBUT capture. This work represents a next step toward the de novo design of solutions to the problem of PBUT management in CKD patients.
doi:10.1101/2020.02.19.940171 fatcat:xnz3vukobzdahhbocyfcztemyu

Molecular Dynamics Simulation and Coarse-Grained Analysis of the Arp2/3 Complex

Jim Pfaendtner, Gregory A. Voth
2008 Biophysical Journal  
A molecular dynamics investigation and coarse-grained analysis of inactivated actin-related protein (Arp) 2/3 complex is presented. It was found that the nucleotide binding site within Arp3 remained in a closed position with bound ATP or ADP, but opened when simulation with no nucleotide was performed. In contrast, simulation of the isolated Arp3 subunit with bound ATP, showed a fast opening of the nucleotide binding cleft. A homology model for the missing subdomains 1 and 2 of Arp2 was
more » ... ted, and it was also found that the Arp2 binding cleft remained closed with bound nucleotide. Within the nucleotide binding cleft a distinct opening and closing period of 10 ns was observed in many of the simulations of Arp2/3 as well as isolated Arp3. Substitution studies were employed, and several alanine substitutions were found to induce a partial opening of the ATP binding cleft in Arp3 and Arp2, whereas only a single substitution was found to induce opening of the ADP binding cleft. It was also found that the nucleotide type did not cause a substantial change on interfacial contacts between Arp3 and the ArpC2, ArpC3 and ArpC4 subunits. Nucleotide-free Arp3 had generally less stable contacts, but the overall contact architecture was constant. Finally, nucleotide-dependent coarse-grained models for Arp3 are developed that serve to further highlight the structural differences induced in Arp3 by nucleotide hydrolysis.
doi:10.1529/biophysj.108.143313 pmid:18805923 pmcid:PMC2586551 fatcat:7z7bkp5nijawzhm4sw4ofc2mwe

Simulation Reveals Fundamental Behavior of the Actin Filament and Arp2/3 Branch Junction

Jim Pfaendtner, Gregory A. Voth
2010 Biophysical Journal  
Pfaendtner, Gregory A.  ...  supported by National Institutes of Health through grants 1U54 -RR022232, P41-RR13186, and 1U54-GM64346-01. 2868-Pos Simulation Reveals Fundamental Behavior of the Actin Filament and Arp2/3 Branch Junction Jim  ... 
doi:10.1016/j.bpj.2009.12.3013 fatcat:whoadpy5hbf6pcxt675ufg54wa

Structural Insights on the Statherin N-Terminal Binding Domain in the Adsorbed State

Michael Deighan, Tobias Weidner, Jim Pfaendtner
2014 Biophysical Journal  
Ca (2þ) -independent phospholipase A2 (iPLA2) is a water-soluble enzyme that is active in association with lipid membranes. The deregulation of iPLA2 causes uncontrolled inflammation that plays a role in a large number of diseases. The design of selective inhibitors of iPLA2 has been complicated by the absence of any X-ray or NMR information about the enzyme structure. Here we have carried out microsecond MD simulations on homology models of iPLA2 to reach a complete understanding of the
more » ... and membrane-related processes associated with the enzyme function and inhibition. The simulations help answer questions that have challenged scientists in this field for decades about the nature of the protein-bilayers complex, the importance of dynamics in the regulation of the active-site pocket, and the detailed mechanism of lipid extraction.
doi:10.1016/j.bpj.2013.11.286 fatcat:cpagzk4psjc53nwoqjl2qus5wi

Determining dominant driving forces affecting controlled protein release from polymeric nanoparticles

Josh Smith, Kayla G. Sprenger, Rick Liao, Andrea Joseph, Elizabeth Nance, Jim Pfaendtner
2017 Biointerphases  
Enzymes play a critical role in many applications in biology and medicine as potential therapeutics. One specific area of interest is enzyme encapsulation in polymer nanostructures, which have applications in drug delivery and catalysis. A detailed understanding of the mechanisms governing protein/polymer interactions is crucial for optimizing the performance of these complex systems for different applications. Using a combined computational and experimental approach, this study aims to
more » ... the relative importance of molecular and mesoscale driving forces to protein release from polymeric nanoparticles. Classical molecular dynamics (MD) simulations have been performed on bovine serum albumin (BSA) in aqueous solutions with oligomeric surrogates of poly(lactic-co-glycolic acid) copolymer, poly(styrene)poly(lactic acid) copolymer, and poly(lactic acid). The simulated strength and location of polymer surrogate binding to the surface of BSA have been compared to experimental BSA release rates from nanoparticles formulated with these same polymers. Results indicate that the self-interaction tendencies of the polymer surrogates and other macroscale properties may play governing roles in protein release. Additional MD simulations of BSA in solution with poly(styrene)-acrylate copolymer reveal the possibility of enhanced control over the enzyme encapsulation process by tuning polymer self-interaction. Last, the authors find consistent protein surface binding preferences across simulations performed with polymer surrogates of varying lengths, demonstrating that protein/polymer interactions can be understood in part by studying the interactions and affinity of proteins with small polymer surrogates in solution.
doi:10.1116/1.4983154 pmid:28525957 pmcid:PMC5648550 fatcat:virm5ypogzd5dnkajeqeuve43q

Defining Coarse-Grained Representations of Large Biomolecules and Biomolecular Complexes from Elastic Network Models

Zhiyong Zhang, Jim Pfaendtner, Andrea Grafmüller, Gregory A. Voth
2009 Biophysical Journal  
Coarse-grained (CG) models of large biomolecular complexes enable simulations of these systems over long timescales that are not accessible for atomistic molecular dynamics (MD) simulations. A systematic methodology, called essential dynamics coarse-graining (ED-CG), has been developed for defining coarse-grained sites in a large biomolecule. The method variationally determines the CG sites so that key dynamic domains in the protein are preserved in the CG representation. The original ED-CG
more » ... od relies on a principal component analysis (PCA) of a MD trajectory. However, for many large proteins and multi-protein complexes such an analysis may not converge or even be possible. This work develops a new ED-CG scheme using an elastic network model (ENM) of the protein structure. In this procedure, the low-frequency normal modes obtained by ENM are used to define dynamic domains and to define the CG representation accordingly. The method is then applied to several proteins, such as the HIV-1 CA protein dimer, ATP-bound G-actin, and the Arp2/3 complex. Numerical results show that ED-CG with ENM (ENM-ED-CG) is much faster than ED-CG with PCA because no MD is necessary. The ENM-ED-CG models also capture functional essential dynamics of the proteins almost as well as those using full MD with PCA. Therefore, the ENM-ED-CG method may be better suited to coarse-grain a very large biomolecule or biomolecular complex that is too computationally expensive to be simulated by conventional MD, or when a high resolution atomic structure is not even available.
doi:10.1016/j.bpj.2009.08.007 pmid:19843465 pmcid:PMC2764101 fatcat:6o37zajtlrbsxdtvqoij4lsvc4

Molecular recognition and specificity of biomolecules to titanium dioxide from molecular dynamics simulations

Janani Sampath, Andrew Kullman, Rachel Gebhart, Gary Drobny, Jim Pfaendtner
2020 npj Computational Materials  
Titania (TiO 2 ) is used extensively in biomedical applications; efforts to boost the biocompatibility of TiO 2 include coating it with the titania binding hexamer, RKLPDA. To understand the binding mechanism of this peptide, we employ molecular dynamics simulations enhanced by metadynamics to study three amino acids present in the peptide-arginine (R), lysine (K), and aspartate (D), on four TiO 2 variants that have different degrees of surface hydroxyl groups. We find that binding is a
more » ... of both sidechain charge and structure, with R binding to all four surfaces, whereas the affinity of K and D is dependent on the distribution of hydroxyl groups. Informed by this, we study the binding of the titania binding hexamer and dodecamer (RKLPDAPGMHTW) on two of the four surfaces, and we see strong correlations between the binding free energy and the primary binding residues, in agreement with prior experiments and simulations. We propose that the discrepancies observed in prior work stem from distribution of surface hydroxyl groups that may be difficult to precisely control on the TiO 2 interface. npj Computational Materials (2020) 6:34 ; https://doi.
doi:10.1038/s41524-020-0288-7 fatcat:fnxsn4b24jbfzarq2pboignfay

A Systematic Methodology for Defining Coarse-Grained Sites in Large Biomolecules

Zhiyong Zhang, Lanyuan Lu, Will G. Noid, Vinod Krishna, Jim Pfaendtner, Gregory A. Voth
2008 Biophysical Journal  
Coarse-grained (CG) models of biomolecules have recently attracted considerable interest because they enable the simulation of complex biological systems on length-scales and timescales that are inaccessible for atomistic molecular dynamics simulation. A CG model is defined by a map that transforms an atomically detailed configuration into a CG configuration. For CG models of relatively small biomolecules or in cases that the CG and all-atom models have similar resolution, the construction of
more » ... is map is relatively straightforward and can be guided by chemical intuition. However, it is more challenging to construct a CG map when large and complex domains of biomolecules have to be represented by relatively few CG sites. This work introduces a new and systematic methodology called essential dynamics coarse-graining (ED-CG). This approach constructs a CG map of the primary sequence at a chosen resolution for an arbitrarily complex biomolecule. In particular, the resulting ED-CG method variationally determines the CG sites that reflect the essential dynamics characterized by principal component analysis of an atomistic molecular dynamics trajectory. Numerical calculations illustrate this approach for the HIV-1 CA protein dimer and ATPbound G-actin. Importantly, since the CG sites are constructed from the primary sequence of the biomolecule, the resulting ED-CG model may be better suited to appropriately explore protein conformational space than those from other CG methods at the same degree of resolution.
doi:10.1529/biophysj.108.139626 pmid:18757560 pmcid:PMC2586547 fatcat:lm5dt6pcpfbnlltzwnqpfmh2ta

Structural Effects of Methionine Oxidation on Isolated Subdomains of Human Fibrin D and αC Regions

Patrick R. Burney, Nathan White, Jim Pfaendtner, Paolo Carloni
2014 PLoS ONE  
Citation: Burney PR, White N, Pfaendtner J (2014) Structural Effects of Methionine Oxidation on Isolated Subdomains of Human Fibrin D and aC Regions. PLoS ONE 9(1): e86981.  ... 
doi:10.1371/journal.pone.0086981 pmid:24475207 pmcid:PMC3903590 fatcat:fqw4wja3ebeyffyv2aijmvtd6a
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