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Dynamic-backbone protein-ligand structure prediction with multiscale generative diffusion models
Zhuoran Qiao · Weili Nie · Arash Vahdat · Thomas Miller · Anima Anandkumar

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in Machine Learning in Structural Biology Workshop »

Molecular complexes formed by proteins and small-molecule ligands are ubiquitous, and predicting their 3D structures can facilitate both biological discoveries and the design of novel enzymes or drug molecules. Here we propose NeuralPLexer, a deep generative model framework to rapidly predict protein-ligand complex structures and their fluctuations using protein backbone template and molecular graph inputs. NeuralPLexer jointly samples protein and small-molecule 3D coordinates at an atomistic resolution through a generative model that incorporates biophysical constraints and inferred proximity information into a time-truncated diffusion process. The reverse-time generative diffusion process is learned by a novel stereochemistry-aware equivariant graph transformer that enables efficient, concurrent gradient field prediction for all heavy atoms in the protein-ligand complex. NeuralPLexer outperforms existing physics-based and learning-based methods on benchmarking problems including fixed-backbone blind protein-ligand docking and ligand-coupled binding site repacking. Moreover, we identify preliminary evidence that NeuralPLexer enriches bound-state-like protein structures when applied to systems where protein folding landscapes are significantly altered by the presence of ligands. Our results reveal that a data-driven approach can capture the structural cooperativity among protein and small-molecule entities, showing promise for the computational identification of novel drug targets and the end-to-end differentiable design of functional small-molecules and ligand-binding proteins.

Author Information

Zhuoran Qiao (Caltech)

I'm a Ph.D. student at Miller Group, Caltech CCE. I'm working on developing deep learning methods with prior physical information for studying challenging problems in molecular electronic structures and dynamics.

Weili Nie (NVIDIA)
Arash Vahdat (NVIDIA Research)
Thomas Miller (Entos, Inc; Caltech)
Anima Anandkumar (NVIDIA / Caltech)

Anima Anandkumar is a Bren professor at Caltech CMS department and a director of machine learning research at NVIDIA. Her research spans both theoretical and practical aspects of large-scale machine learning. In particular, she has spearheaded research in tensor-algebraic methods, non-convex optimization, probabilistic models and deep learning. Anima is the recipient of several awards and honors such as the Bren named chair professorship at Caltech, Alfred. P. Sloan Fellowship, Young investigator awards from the Air Force and Army research offices, Faculty fellowships from Microsoft, Google and Adobe, and several best paper awards. Anima received her B.Tech in Electrical Engineering from IIT Madras in 2004 and her PhD from Cornell University in 2009. She was a postdoctoral researcher at MIT from 2009 to 2010, a visiting researcher at Microsoft Research New England in 2012 and 2014, an assistant professor at U.C. Irvine between 2010 and 2016, an associate professor at U.C. Irvine between 2016 and 2017 and a principal scientist at Amazon Web Services between 2016 and 2018.

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