# Core B - Computational Biology

> **NIH NIH P01** · VANDERBILT UNIVERSITY MEDICAL CENTER · 2020 · $429,095

## Abstract

The central hypothesis of this Program Project Grant is that HDL's platform protein, apoA-I, is a conformationally
dynamic scaffold that facilitates interactions among other HDL proteins and lipid remodeling factors that exert
potent biological effects on the artery wall. Our objective is to empower a multidisciplinary team to understand, in
unprecedented detail, HDL's structure, function, assembly and dynamics, including the molecular mechanisms
that enable apoA-I to function as a platform. Our proposed research program centers on three topics: Project 1:
Structural basis of HDL assembly―Jere Segrest, Project Leader (UAB); Project 2: Structural basis of HDL
maturation―W. Sean Davidson, Project Leader (U. Cincinnati); Project 3: HDL structure/function in LCAT
deficient humans ―Jay Heinecke, Project Leader (U. Washington). These three topics involve the dynamic
interactions among three world-class scientists with unique (and complementary) areas of expertise all studying
HDL, a unique collaboration unlikely to exist at any single institution and rare in science and in the HDL field.
Each project has proposed several collaborative studies among projects that would not be possible in the
absence of a PPG. The Computational Biology Core B will provide high-end computational support for the
three projects, focusing on computational simulations and molecular modeling. To achieve these objectives, we
propose the following specific aims: 1) To create the starting structure and perform molecular dynamics (MD)
simulations of molecular models relevant to each project. 2) To simulate discoidal and spheroidal HDL particles
and study their interactions with models of LCAT (Heinecke), CETP, apoA-II and PON1 (Davidson), and PLTP
(Segrest). 3) To fit mass spectroscopy-cross linking data to model MD simulations (Segrest, Davidson, and
Heinecke) using the sum of violation distances method to judge goodness of fit. 4) To provide a method for
increasing surface pressure on one side of a periodic bilayer (Segrest). 5) To create homology models of LCAT
(Segrest and Heinecke), humanized PON1 (Davidson), ABCA1 and PLTP (Segrest). 6) To use normal mode
analysis to explore possible transitional states for homology models of the open and closed forms of ABCA1
(Segrest); to analyze possible domain motions in, e.g., the opening and closing of the active site “lid” and the
sn-2 acyl chain binding cleft in LCAT (Heinecke), and to explore possible transition states in humanized PON1,
CETP and apoA-II (Davidson) and PLTP (Segrest). 7) To use the program LOCATE to analyze amphipathic
motifs to develop models for ABCA1 (Segrest) and apoA-II (Davidson), and to analyze possible lipid-
associating domains in PON1 and CETP (Davidson), and PLTP (Segrest). 8) To use the Rosetta Protein
Modeling Suite for ab initio modeling of small protein domains and docking ligands to protein models of interest
(Segrest, Davidson and Heinecke).

## Key facts

- **NIH application ID:** 9951094
- **Project number:** 5P01HL128203-05
- **Recipient organization:** VANDERBILT UNIVERSITY MEDICAL CENTER
- **Principal Investigator:** Martin K Jones
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $429,095
- **Award type:** 5
- **Project period:** — → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9951094

## Citation

> US National Institutes of Health, RePORTER application 9951094, Core B - Computational Biology (5P01HL128203-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9951094. Licensed CC0.

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