We present a framework, which we call Molecule Deep Q-Networks (MolDQN), for molecule optimization by combining domain knowledge of chemistry and state-of-the-art reinforcement learning techniques ...(double Q-learning and randomized value functions). We directly define modifications on molecules, thereby ensuring 100% chemical validity. Further, we operate without pre-training on any dataset to avoid possible bias from the choice of that set. MolDQN achieves comparable or better performance against several other recently published algorithms for benchmark molecular optimization tasks. However, we also argue that many of these tasks are not representative of real optimization problems in drug discovery. Inspired by problems faced during medicinal chemistry lead optimization, we extend our model with multi-objective reinforcement learning, which maximizes drug-likeness while maintaining similarity to the original molecule. We further show the path through chemical space to achieve optimization for a molecule to understand how the model works.
Protein-inorganic hybrid nanoflowers Ge, Jun; Lei, Jiandu; Zare, Richard N
Nature nanotechnology,
2012-Jun-03, Letnik:
7, Številka:
7
Journal Article
Recenzirano
Flower-shaped inorganic nanocrystals have been used for applications in catalysis and analytical science, but so far there have been no reports of 'nanoflowers' made of organic components. Here, we ...report a method for creating hybrid organic-inorganic nanoflowers using copper (II) ions as the inorganic component and various proteins as the organic component. The protein molecules form complexes with the copper ions, and these complexes become nucleation sites for primary crystals of copper phosphate. Interaction between the protein and copper ions then leads to the growth of micrometre-sized particles that have nanoscale features and that are shaped like flower petals. When an enzyme is used as the protein component of the hybrid nanoflower, it exhibits enhanced enzymatic activity and stability compared with the free enzyme. This is attributed to the high surface area and confinement of the enzymes in the nanoflowers.
Bulk water serves as an inert solvent for many chemical and biological reactions. Here, we report a striking exception. We observe that in micrometer-sized water droplets (microdroplets), spontaneous ...reduction of several organic molecules occurs, pyruvate to lactate, lipoic acid to dihydrolipoic acid, fumarate to succinate, and oxaloacetate to malate. This reduction proceeds in microdroplets without any added electron donors or acceptors and without any applied voltage. In three of the four cases, the reduction efficiency is 90% or greater when the concentration of the dissolved organic species is less than 0.1 μM. None of these reactions occurs spontaneously in bulk water. One example demonstrating the possible broad application of reduction in water microdroplets to organic molecules is the reduction of acetophenone to form 1-phenylethanol. Taken together, these results show that microdroplets provide a new foundation for green chemistry by rendering water molecules to be highly electrochemically active without any added reducing agent or applied potential. In this manner, aqueous microdroplets might have provided a route for abiotic reduction reactions in the prebiotic era, thereby providing organic molecules with a reducing power before the advent of biotic reducing machineries.
Chemical reactions in aqueous microdroplets often exhibit unusual kinetic and thermodynamic properties not observed in bulk solution. While an electric field has been implicated at the water ...interface, there has been no direct measurement in aqueous microdroplets, largely due to the lack of proper measurement tools. Herein, we employ newly developed stimulated Raman excited fluorescence microscopy to measure the electric field at the water–oil interface of microdroplets. As determined by the vibrational Stark effect of a nitrile-bearing fluorescent probe, the strength of the electric field is found to be on the order of 107 V/cm. This strong electric field aligns probe dipoles with respect to the interface. The formation of the electric field likely arises from charge separation caused by the adsorption of negative ions at the water–oil interface of microdroplets. We suggest that this strong electric field might account in part for the unique properties of chemical reactions reported in microdroplets.
A Pomeranz–Fritsch synthesis of isoquinoline and Friedländer and Combes syntheses of substituted quinolines were conducted in charged microdroplets produced by an electrospray process at ambient ...temperature and atmospheric pressure. In the bulk phase, all of these reactions are known to take a long time ranging from several minutes to a few days and to require very high acid concentrations. In sharp contrast, the present report provides clear evidence that all of these reactions occur on the millisecond timescale in the charged microdroplets without the addition of any external acid. Decreasing the droplet size and increasing the charge of the droplet both strongly contribute to reaction rate acceleration, suggesting that the reaction occurs in a confined environment on the charged surface of the droplet.
Microdroplet chemistry: Isoquinolines and quinolines can be synthesized in charged microdroplets during a flight time on the order of a few milliseconds without the addition of external acid as a catalyst. The surface characteristics of the microdroplet are shown to play a critical role in accomplishing these reactions at enhanced rates.
We report the use of 1,2,3-triazole (Tz)-containing water microdroplets for gas-phase carbon dioxide (CO2) reduction at room temperature. Using a coaxial sonic spraying setup, the CO2 can be ...efficiently captured by Tz and converted to formic acid (HCOOH; FA) at the gas–liquid interface (GLI). A mass spectrometer operated in negative ion mode monitors the capture of CO2 to form the bicarbonate anion (HCO3 –) and conversion to form the formate anion (HCOO–). Varied FA species were successfully identified by MS/MS experiments including the formate monomer (FA – H−, m/z 45), the dimer (2FA – H−, m/z 91; 2FA + Na – 2H−, m/z 113), the trimer (3FA – H−, m/z 137), and some other adducts (such as FA – H + H2CO3−, m/z 107; 2FA + Na – 2H + Tz−, m/z 182). The reaction conditions were systematically optimized to make the maximum conversion yield reach over 80% with an FA concentration of approximately 71 ± 3.1 μM. The mechanism for the reaction is speculated to be that Tz donates the proton and the hydroxide (OH–) at the GLI, resulting in a stepwise yield of electrons to reduce gas-phase CO2 to FA.
Enzymatic digestion for protein sequencing usually requires much time, and does not always result in high sequence coverage. Here we report the use of aqueous microdroplets to accelerate enzymatic ...reactions and, in particular, to improve protein sequencing. When a room temperature aqueous solution containing 10 µM myoglobin and 5 µg mL
trypsin is electrosonically sprayed (-3 kV) from a homemade setup to produce tiny (∼9 µm) microdroplets, we obtain 100% sequence coverage in less than 1 ms of digestion time, in sharp contrast to 60% coverage achieved by incubating the same solution at 37 °C for 14 h followed by analysis with a commercial electrospray ionization source that produces larger (∼60 µm) droplets. We also confirm the sequence of the therapeutic antibody trastuzumab (∼148 kDa), with a sequence coverage of 100% for light chains and 85% for heavy chains, demonstrating the practical utility of microdroplets in drug development.
Deep reinforcement learning was employed to optimize chemical reactions. Our model iteratively records the results of a chemical reaction and chooses new experimental conditions to improve the ...reaction outcome. This model outperformed a state-of-the-art blackbox optimization algorithm by using 71% fewer steps on both simulations and real reactions. Furthermore, we introduced an efficient exploration strategy by drawing the reaction conditions from certain probability distributions, which resulted in an improvement on regret from 0.062 to 0.039 compared with a deterministic policy. Combining the efficient exploration policy with accelerated microdroplet reactions, optimal reaction conditions were determined in 30 min for the four reactions considered, and a better understanding of the factors that control microdroplet reactions was reached. Moreover, our model showed a better performance after training on reactions with similar or even dissimilar underlying mechanisms, which demonstrates its learning ability.
Making ammonia from nitrogen and water microdroplets Song, Xiaowei; Basheer, Chanbasha; Zare, Richard N
Proceedings of the National Academy of Sciences - PNAS,
04/2023, Letnik:
120, Številka:
16
Journal Article
Recenzirano
Odprti dostop
Water (H
O) microdroplets are sprayed onto a magnetic iron oxide (Fe
O
) and Nafion-coated graphite mesh using compressed N
or air as the nebulizing gas. The resulting splash of microdroplets enters ...a mass spectrometer and is found to contain ammonia (NH
). This gas-liquid-solid heterogeneous catalytic system synthesizes ammonia in 0.2 ms. The conversion rate reaches 32.9 ± 1.38 nmol s
cm
at room temperature without application of an external electric potential and without irradiation. Water microdroplets are the hydrogen source for N
in contact with Fe
O
. Hydrazine (H
NNH
) is also observed as a by-product and is suspected to be an intermediate in the formation of ammonia. This one-step nitrogen-fixation strategy to produce ammonia is eco-friendly and low cost, which converts widely available starting materials into a value-added product.
Quantum control of molecular collisions at 1 kelvin Perreault, William E.; Mukherjee, Nandini; Zare, Richard N.
Science (American Association for the Advancement of Science),
10/2017, Letnik:
358, Številka:
6361
Journal Article
Recenzirano
Measurement of vector correlations in molecular scattering is an indispensable tool for mapping out interaction potentials. In a coexpanded supersonic beam, we have studied the rotationally inelastic ...process wherein deuterium hydride (HD) (v = 1, j = 2) collides with molecular deuterium (D₂) to form HD (v = 1, j = 1), where v and j are the vibrational and rotational quantum numbers, respectively. HD (v = 1, j = 2) was prepared by Stark-induced adiabatic Raman passage, with its bond axis aligned preferentially parallel or perpendicular to the lab-fixed relative velocity. The coexpansion brought the collision temperature down to 1 kelvin, restricting scattering to s and p partial waves. Scattering angular distributions showed a dramatic stereodynamic preference (~3:1) for perpendicular versus parallel alignment. The four-vector correlation measured between the initial and final velocities and the initial and final rotational angular momentum vectors of HD provides insight into the strong anisotropic forces present in the collision process.
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