ChE PhD Dissertation Defense: Natesan Mani

Name:
Natesan Mani

Title:
A Tale of Two Fcs: Investigating Furin cleavage in the SARS-CoV-2 Spike Protein and Glycan Effects in IgG Fcs

Date:
06/24/2026

Time:
12:30:00 PM

Committee Members:
Prof. Srirupa Chakraborty (Advisor)
Prof. Francisco Hung
Prof. Sunny Zhou
Dr. Alla Polozova

Location:
409 Robinson Hall

Abstract:
This dissertation examines critical structural dynamics in viral infection and antibody-mediated immune response using Molecular Dynamics (MD) simulations. We investigated two distinct but fundamentally related systems: the SARS-CoV-2 Spike protein with emphasis on Furin cleavage (the antigen Fc), and the IgG1 Fc-CD16a receptor interaction with varying glycosylation profiles (the antibody Fc).

Antigen Study: The SARS-CoV-2 Spike protein’s furin cleavage site (FCS) is a defining feature that distinguishes it from its predecessor SARS-CoV and is critical to viral infectivity. While extensive vaccine research has utilized stabilized Spike constructs with mutated or deleted FCS, physiologically, the cleavage occurs during viral particle formation. Using large-scale atomistic MD simulations of both Furin Cleaved and Uncleaved Spike proteins in the receptor-binding domain (RBD) Open and Closed conformations, we demonstrate that furin cleavage fundamentally alters the Spike protein’s conformational dynamics. We observe increased correlated motions between the RBD and N-terminal domain (NTD) in the Furin Cleaved systems, enhanced RBD sampling of exposed conformations favorable for ACE2 binding and altered glycan clustering patterns on key N-linked glycans. These observations provide quantitative evidence that cleavage primes the Spike protein for membrane fusion and enhances receptor accessibility. These findings provide a mechanistic foundation for designing immunogens and therapeutics targeting not only SARS-CoV-2 but also emerging Sarbecoviruses and related viral families.

Antibody Study: IgG1 is the predominant antibody subclass used in therapeutic applications, with its Fc region mediating critical effector functions including antibody-dependent cellular cytotoxicity (ADCC) through CD16a receptor engagement on natural killer cells. The glycosylation profiles of both the IgG1 Fc and CD16a receptor play essential roles in determining binding affinity and immune response magnitude. Using MD simulations of 22 distinct glycoform combinations, we systematically examine how variations in core fucosylation and terminal galactosylation affect Fc-CD16a complex formation and stability. We evaluate the structural impact of asymmetric binding between the two Fc arms and the receptor, calculate binding affinities and correlate structural observations with binding energetics. Our results validate known trends (afucosylation enhancement) while revealing nuanced effects of galactosylation and chain-specific glycan positioning. Together, these findings and the accompanying mechanistic framework provide a foundation for the glycan-informed rational design of next-generation antibody therapeutics with enhanced immune potency

Together, these studies demonstrate how atomistic molecular dynamics can bridge gaps between structural biology and functional outcomes, providing quantitative frameworks for designing improved viral vaccines and enhanced therapeutic antibodies. The methodologies and insights presented here have broad applicability to understanding glycoprotein-receptor interactions across biological systems.

Natesan Mani is a PhD candidate in Chemical Engineering at Northeastern University, where he expects to defend in June 2026. He completed his M.S. in Chemical Engineering at the University of Houston in 2020 and earned his B.S. in Chemical Engineering from Osmania University in India in 2019. His doctoral research in the SimBioSys Lab at Northeastern University focuses on developing physics-informed computational tools that combine molecular dynamics (MD) simulations and machine learning to predict molecular properties and guide the design of high-affinity antibodies, work conducted in direct collaboration with Amgen’s Pivotal Attribute Sciences team. Natesan has gained significant industry experience through internships at Amgen, where he modeled antibody-receptor interfaces and developed GPU-accelerated simulation pipelines, and at Prescient Design (Genentech), where he built multi-modal biological data frameworks to inform therapeutic design decisions. He has authored one first-author manuscript in Protein Science, has two manuscripts under review, and has presented his research at over five national conferences, including BPS, AIChE, and ACS. He is also the creator of F.A.D.E (Fully Agentic Drug Engine), a prize-winning integrated modelling framework recognized at the Broad Institute ML Symposium and selected for presentation at ACS SciMix and ACS COMP. Beyond his research, Natesan is an active leader in his academic community. He founded the Northeastern Biophysical Society student chapter and served as its President in 2025. He also served as a Treasurer of the ChemE Graduate Student Council. He has been recognized with numerous honours, including the LEADERs Fellowship, NSF ACCESS Award, multiple travel grants and recognition from both the Department of Chemical Engineering and the University.