Justin Lemkul

Justin Lemkul
Virginia Polytechnic Institute and State University | VT · Department of Biochemistry

Ph.D., Biochemistry

About

79
Publications
467,546
Reads
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4,367
Citations
Introduction
Research in my laboratory focuses on applying cutting-edge polarizable force fields to proteins and nucleic acids to gain greater insight into conformational ensembles and driving forces for folding and stability. We aim to understand disease states with these powerful models and use this information to drive computer-aided drug design. I am a GROMACS developer and currently use GROMACS, OpenMM, NAMD, and CHARMM for my work.
Additional affiliations
February 2018 - June 2019
Virginia Polytechnic Institute and State University
Position
  • Instructor
Description
  • Instructor of record for BCHM 4784/5784G Advanced Applications in Molecular Life Sciences.
September 2017 - March 2020
Virginia Polytechnic Institute and State University
Position
  • Professor (Assistant)
August 2013 - August 2017
University of Maryland, Baltimore
Position
  • PostDoc Position
Education
September 2007 - June 2012
September 2003 - June 2007

Publications

Publications (79)
Article
Molecular mechanics force fields that explicitly account for induced polarization represent the next generation of physical models for molecular dynamics simulations. Several methods exist for modeling induced polarization, and here we review the classical Drude oscillator model, in which electronic degrees of freedom are modeled by charged particl...
Article
Empirical force fields seek to relate the configuration of a set of atoms to its energy, thus yielding the forces governing its dynamics, using classical physics rather than more expensive quantum mechanical calculations that are computationally intractable for large systems. Most force fields used to simulate biomolecular systems use fixed atomic...
Article
The structure and dynamics of DNA are governed by a sensitive balance between base stacking and pairing, hydration, and interactions with ions. Force field models that include explicit representations of electronic polarization are capable of more accurately modeling the subtle details of these interactions versus commonly used additive force field...
Article
RNA molecules are highly dynamic and capable of adopting a wide range of complex, folded structures. The factors driving the folding and dynamics of these structures are dependent on a balance of base pairing, hydration, base stacking, ion interactions, and the conformational sampling of the 2′‐hydroxyl group in the ribose sugar. The representation...
Article
G-quadruplexes (GQs) are highly ordered nucleic acid structures that play fundamental roles in regulating gene expression and maintaining genomic stability. GQs are topologically diverse and enriched in promoter sequences of growth regulatory genes and proto-oncogenes, suggesting they may serve as attractive targets for drug design at the level of...
Article
Familial Alzheimer's disease (FAD) mutations of the amyloid β-peptide (Aβ) are known to lead to early onset and more aggressive Alzheimer's disease. FAD mutations such as "Iowa" (D23N), "Arctic" (E22G), "Italian" (E22K), and "Dutch" (E22Q) have been shown to accelerate Aβ aggregation relative to the wild-type (WT). The mechanism by which these muta...
Article
Full-text available
Telomeric DNA is guanine-rich and can adopt structures such as G-quadruplexes (GQs) and G-hairpins. Telomeric GQs influence genome stability and telomerase activity, making understanding of enzyme-GQ interactions and dynamics important for potential drug design. GQs have a characteristic tetrad core, which is connected by loop regions. Within this...
Article
Intrinsically disordered proteins (IDPs) are an abundant class of highly charged proteins that participate in numerous crucial biological processes, often in regulatory roles. IDPs do not have one major free energy minimum with a dominant structure, instead existing as conformational ensembles of multiple semistable conformations. p53 is a prototyp...
Preprint
Familial Alzheimer’s disease (FAD) mutations of the amyloid β -peptide (A β ) are known to lead to early onset and more aggressive Alzheimer’s disease. FAD mutations such as “Iowa” (D23N), “Arctic” (E22G), “Italian” (E22K), and “Dutch” (E22Q) have been shown to accelerate A β aggregation relative to the wild-type (WT). The mechanism by which these...
Article
We introduce TUPÃ, a Python‐based algorithm to calculate and analyze electric fields in molecular simulations. To demonstrate the features in TUPÃ, we present three test cases in which the orientation and magnitude of the electric field exerted by biomolecules help explain biological phenomena or observed kinetics. As part of TUPÃ, we also provide...
Article
Full-text available
The development of accurate protein force fields has been the cornerstone of molecular simulations for the past 50 years. During this period, many lessons have been learned regarding the use of experimental target data and parameter fitting procedures. Here, we review recent advances in protein force field development. We discuss the recent emergen...
Article
Explicit treatment of electronic polarizability in empirical force fields (FFs) represents an extension over a traditional additive or pairwise FF and provides a more realistic model of the variations in electronic structure in condensed phase, macromolecular simulations. To facilitate utilization of the polarizable FF based on the classical Drude...
Article
Amyloids are a subset of intrinsically disordered proteins (IDPs) that self-assemble into cross-β oligomers and fibrils. The structural plasticity of amyloids leads to sampling of metastable, low-molecular-weight oligomers that contribute to cytotoxicity. Of interest are amyloid-β (Aβ) and islet amyloid polypeptide (IAPP), which are involved in the...
Chapter
Molecular dynamics (MD) simulations performed with force fields that include explicit electronic polarization are becoming more prevalent in the field. The increasing emergence of these simulations is a result of continual refinement against a range of theoretical and empirical target data, optimization of software algorithms for higher performance...
Article
Full-text available
Nucleic acid-ion interactions are fundamentally important to the physical, energetic, and conformational properties of DNA and RNA. These interactions help fold and stabilize highly ordered secondary and tertiary structures, such as G-quadruplexes (GQs), which are functionally relevant in telomeres, replication initiation sites, and promoter sequen...
Article
G-quadruplexes (GQs) are topologically diverse, highly thermostable noncanonical nucleic acid structures that form in guanine-rich sequences in DNA and RNA. GQs are implicated in transcriptional and translational regulation and genome maintenance, and deleterious alterations to their structures contribute to diseases such as cancer. The expression...
Article
Nucleic acids play critical roles in carrying genetic information, participating in catalysis, and preserving chromosomal structure. Despite over a century of study, efforts to understand the dynamics and structure-function relationships of DNA and RNA at the atomic level are still ongoing. Molecular dynamics (MD) simulations augment experiments by...
Article
Full-text available
Bending and twisting around carbon-carbon single bonds are ubiquitous in natural and synthetic polymers. Force-induced changes were so far not measured at the single-monomer level, owing to limited ways to apply local forces. We quantified down to the sub-molecular level the mechanical response within individual poly-pyrenylene chains upon their de...
Chapter
Protein force fields have been undergoing continual development since the first complete parameter sets were introduced nearly four decades ago. The functional forms that underlie these models have many common elements for the treatment of bonded and nonbonded forces, which are reviewed here. The most widely used force fields to date use a fixed-ch...
Article
Full-text available
DNA and RNA sequences rich in guanine can fold into noncanonical structures called G-quadruplexes (GQs), which exhibit a common stem structure of Hoogsteen hydrogen-bonded guanine tetrads and diverse loop structures. GQ sequence motifs are overrepresented in promoters, origins of replication, telomeres, and untranslated regions in mRNA, suggesting...
Conference Paper
Full-text available
Research in life science domains is producing larger data sets that require the use of computational approaches to understand biological phenomena. Academic institutions, industry, and other sectors in the life sciences are creating jobs that involve computation, data science, and data visualization. Therefore, there is a need for life scientists t...
Article
Full-text available
Fusobacterium necrophorum is a pathogenic Gram-negative, anaerobic bacterium. In this study, we present the first complete genome sequence of Fusobacterium necrophorum subsp. necrophorum ATCC 25286. These data provide a critical advancement in our understanding of virulence factors that could contribute to F. necrophorum pathogenesis in both human...
Article
Guanine-quadruplexes (GQs) are guanine-rich, noncanonical nucleic acid structures that play fundamental roles in genomic stability and the regulation of gene expression. GQs are enriched in promoter sequences of growth regulatory genes and proto-oncogenes such as c-kit, which is linked to gastrointestinal stromal tumors, mast cell disease, and leuk...
Article
Spectroscopic analysis of compounds is typically combined with density functional the- ory, for instance for assigning vibrational frequencies, limiting application to relatively small compounds. Accurate classical force fields could, in principle, complement these quantum- chemical tools. A relatively simple way to validate vibrational frequencies...
Article
Full-text available
Here we present FusoPortal, an interactive repository of Fusobacterium genomes that were sequenced using a hybrid MinION long-read sequencing pipeline, followed by assembly and annotation using a diverse portfolio of predominantly open-source software. Significant efforts were made to provide genomic and bioinformatic data as downloadable files, in...
Article
The gp41 transmembrane domain (TMD) of the envelope glycoprotein of the human immunodeficiency virus modulates the conformation of the viral envelope spike, the only druggable target on the surface of the virion. Targeting the envelope glycoprotein with small-molecule and antibody therapies requires an understanding of gp41 TMD dynamics, which is o...
Article
Presented is the implementation of the Drude force field in the open‐source OpenMM simulation package allowing for access to graphical processing unit (GPU) hardware. In the Drude model, electronic degrees of freedom are represented by negatively charged particles attached to their parent atoms via harmonic springs, such that extra computational ov...
Article
Pathological aggregation of amyloid-forming proteins is a hallmark of a number of human diseases, including Alzheimer's, type 2 diabetes, Parkinson's, and more. Despite having very different primary amino acid sequences, these amyloid proteins form similar supramolecular, fibril structures that are highly resilient to physical and chemical denatura...
Preprint
Full-text available
Here we present FusoPortal, an interactive repository of Fusobacterium genomes that were sequenced using a hybrid MinION long-read sequencing pipeline, followed by assembly and annotation using a diverse portfolio of predominantly open-source software. Significant efforts were made to provide genomic and bioinformatic data as downloadable files, in...
Preprint
Full-text available
The gp41 transmembrane domain (TMD) of the envelope glycoprotein (Env) of the human immunodeficiency virus (HIV) modulates the conformation of the viral envelope spike, the only druggable target on the surface of the virion. Understanding of TMD dynamics is needed to better probe and target Env with small molecule and antibody therapies. However, l...
Article
Full-text available
Fosfomycin exhibits broad-spectrum antibacterial activity, and is being re-evaluated for the treatment of extensively drug-resistant pathogens. Its activity in Gram-negatives, however, can be compromised by expression of FosA, a metal-dependent transferase that catalyzes the conjugation of glutathione to fosfomycin, rendering the antibiotic inactiv...
Article
Binding of metal ions is an important factor governing the folding and dynamics of RNA. Shielding of charges in the polyanionic backbone allows RNA to adopt a diverse range of folded structures that give rise to their many functions within the cell. Some RNA sequences fold only in the presence of Mg²⁺, which may be bound via direct interactions or...
Article
Mg2+ ions are important in biological systems, particularly in stabilizing compact RNA folds. Mg2+ is strongly polarizing, and representing its interactions in heterogeneous environments is a challenge for empirical force field development. To date, the most commonly used force fields in molecular dynamics simulations utilize a pairwise-additive ap...
Article
Full-text available
A halogen bond is a highly directional, non-covalent interaction between a halogen atom and another electronegative atom. It arises due to the formation of a small region of positive electrostatic potential opposite the covalent bond to the halogen, called the ‘sigma hole.’ Empirical force fields in which the electrostatic interactions are represen...
Article
Amyloid-forming proteins undergo a structural transition from α-helical to disordered conformations, and ultimately cross-β fibrils. The unfolding and aggregation of the amyloid β-peptide (Aβ) have been implicated in the development and progression of Alzheimer's disease (AD) and cerebral amyloid angiopathy (CAA). However, the events underlying the...
Article
The conformational dynamics of a macromolecule can be modulated by a number of factors, including changes in environment, ligand binding, and interactions with other macromolecules, among others. We present a method that quantifies the differences in macromolecular conformational dynamics and automatically extracts the structural features responsib...
Article
Full-text available
Proper treatment of nonbonded interactions is essential for the accuracy of molecular dynamics (MD) simulations, especially in studies of lipid bilayers. The use of the CHARMM36 force field (C36 FF) in different MD simulation programs can result in disagreements with published simulations performed with CHARMM due to differences in the protocols us...
Article
Full-text available
Peroxisome-proliferator activated receptor-γ (PPARγ) is a nuclear hormone receptor that forms a heterodimeric complex with retinoid X receptor-α (RXRα) to regulate transcription of genes involved in fatty acid storage and glucose metabolism. PPARγ is a target for pharmaceutical intervention in type 2 diabetes, and insight into interactions between...
Article
Explicit treatment of electronic polarization in empirical force fields used for molecular dynamics simulations represents an important advancement in simulation methodology. A straightforward means of treating electronic polarization in these simulations is the inclusion of Drude oscillators, which are auxiliary, charge-carrying particles bonded t...
Poster
RNA plays many important roles in the cell, including information transfer, gene regulation, protein synthesis, and catalysis. This diversity in function arises in part from the adoption of complex tertiary structures and interconversion between multiple conformational states in response to bound metabolites or changes in other cellular conditions....
Book
Full-text available
GROMACS (GROningen MAchine for Chemical Simulations) is a molecular dynamics package primarily designed for simulations of proteins, lipids and nucleic acids. It was originally developed in the Biophysical Chemistry department of University of Groningen, and is now maintained by contributors in universities and research centers across the world.
Article
Base flipping in DNA is an important process involved in genomic repair and epigenetic control of gene expression. The driving forces for these processes are not fully understood, especially in the context of the underlying dynamics of the DNA and solvent effects. We studied double-stranded DNA oligomers that have been previously characterized by i...
Article
Full-text available
The Wnt-dependent, β-catenin-independent pathway modulates cell movement and behavior. A downstream regulator of this signaling pathway is Dishevelled (Dvl), which, among other multiple interactions, binds to the Frizzled receptor and the plasma membrane via phosphatidic acid (PA) in a mechanism proposed to be pH-dependent. While the Dvl DEP domain...
Article
The amyloid β-peptide (Aβ) is a 40-42 residue peptide that is the principal toxic species in Alzheimer's disease (AD). The oxidation of methionine-35 (Met35) to the sulfoxide form (Met35(ox)) has been identified as potential modulator of Aβ aggregation. The role Met35(ox) plays in Aβ neurotoxicity differs among experimental studies, which may be du...
Article
Macromolecular function arises from structure, and many diseases are associated with misfolding of proteins. Molecular simulation methods can augment experimental techniques to understand misfolding and aggregation pathways with atomistic resolution, but the reliability of these predictions is a function of the parameters used for the simulation. T...
Article
Numerous studies have concluded that the interaction of the amyloid β-peptide (Aβ) and cellular membranes contributes to the toxicity and cell death observed in the progression of Alzheimer's disease. Aggregated Aβ species disrupt membranes, leading to physical instability and ion leakage. Further, the presence of Aβ on the membrane surface increas...
Article
The pathogenic aggregation of the amyloid β-peptide (Aβ) is considered a hallmark of the progression of Alzheimer's disease, the leading cause of senile dementia in the elderly and one of the principal causes of death in the United States. In the absence of effective therapeutics, the incidence and economic burden associated with the disease are ex...
Article
Alzheimer's disease is a debilitating neurodegenerative disorder whose pathology has been linked to the aggregation and deposition of the amyloid β-peptide (Aβ) in neural tissue. A truly effective therapeutic agent remains elusive, and attention has recently turned to the use of natural products as effective antiaggregation compounds, directly targ...
Article
The behavior of the amyloid β-peptide (Aβ) within a membrane environment is integral to its toxicity and the progression of Alzheimer's disease. Ganglioside GM1 has been shown to enhance the aggregation of Aβ, but the underlying mechanism is unknown. Using atomistic molecular dynamics simulations, we explored the interactions between the 40-residue...
Article
Type IV pili are important adhesion and motility factors in both gram-negative and gram-positive bacterial species, making pilus assembly from pilin subunits an important biophysical mechanism to understand at an atomic level. Knowledge of the pilus assembly mechanism has applications in antibiotic development, microbial physiology, and systems bio...
Article
Molecular dynamics simulations are being applied to increasingly complex systems, including those involving small endogenous compounds and drug molecules. In order to obtain meaningful and accurate data from these simulations, high-quality topologies for small molecules must be generated in a manner that is consistent with the derivation of the for...
Article
Full-text available
Tyrosine aminotransferase (TAT) catalyzes the transamination of tyrosine and other aromatic amino acids. The enzyme is thought to play a role in tyrosinemia type II, hepatitis and hepatic carcinoma recovery. The objective of this study is to investigate its biochemical and structural characteristics and substrate specificity in order to provide ins...
Article
Alzheimer's disease is a progressive, neurodegenerative disorder that is the leading cause of senile dementia, afflicting millions of individuals worldwide. Since the identification of the amyloid beta-peptide (Abeta) as the principal toxic entity in the progression of Alzheimer's disease, numerous attempts have been made to reduce endogenous Abeta...
Article
Amyloid fibrils represent a stable form of many misfolded proteins associated with numerous diseases. Among these are Parkinson's disease (alpha-synuclein), Type II diabetes (islet amyloid polypeptide), and Alzheimer's disease (amyloid beta-peptide, Abeta). The appearance of Abeta fibrils in neural tissue is a hallmark of Alzheimer's disease, and m...
Article
GridMAT-MD is a new program developed to aid in the analysis of lipid bilayers from molecular dynamics simulations. It reads a GROMACS coordinate file and generates two types of data: a two-dimensional contour plot depicting membrane thickness, and a polygon-based tessellation of the individual lipid headgroups. GridMAT-MD can also account for prot...
Article
The etiology of Alzheimer's disease is considered to be linked to interactions between amyloid beta-peptide (Abeta) and neural cell membranes. Membrane disruption and increased ion conductance have been observed in vitro in the presence of Abeta, and it is assumed that these same phenomena occur in the brain of an individual afflicted with Alzheime...
Article
Because the amyloid beta-peptide (Abeta) functions as approximately half of the transmembrane domain of the amyloid precursor protein and interaction of Abeta with membranes is proposed to result in neurotoxicity, the association of Abeta with membranes likely is important in the etiology of Alzheimer's disease. Atomic details of the interaction of...

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Projects

Projects (4)
Project
Our project provides unique learning resources to promote scientific literacy, STEM engagement, and diverse workforce development. We generate computer-based renderings of biomolecules that can be viewed in two and three dimensions. To further enhance the learning process and facilitate the incorporation of concepts of biomolecular structures in the classroom, we also develop resources for teachers at the primary and secondary levels. These resources can be found on our OSF page (https://osf.io/pq86x/) and are available for all to use.
Project
The goal of this project is to advance simulation technology through the development and open availability of tools and protocols to further MD simulations and to rapidly and rigorously analyze their results.
Project
The collective aim of these studies is to understand how amyloidogenic proteins unfold, aggregate, and interact with each other and cellular components such as the plasma membrane. MD simulations are central to this goal as they provide an atomistic view of these pathways and can generate new information for drug design. New developments in polarizable force fields are yielding unprecedented insight.