About

Yale E. Goldman, MD, PhD, is an Emeritus Professor of Physiology at the University of Pennsylvania's Perelman School of Medicine. He is a member of the Pennsylvania Muscle Institute and serves as Co-Director of the Nano-Bio Interface Center at the University of Pennsylvania. His research focuses on relating structural changes to enzymatic reactions and mechanical steps of energy transduction mechanisms by mapping real-time domain motions of motor proteins and ribosomal elongation factors. Goldman investigates molecular motors such as myosin, kinesin, and dynein, which are prototype biological energy transducers, using novel biophysical techniques including nanometer tracking of single fluorescent molecules, bifunctional fluorescent probes, and infrared optical traps to understand their structural dynamics and function. His work extends to studying the ribosome, a motor involved in protein biosynthesis, particularly how it achieves high fidelity during messenger RNA translation into amino acid sequences. His research explores how energy from GTP splitting by elongation factors is transformed into translational accuracy and maintenance of the reading frame. Goldman’s contributions include elucidating the mechanisms of motor proteins and GTP-binding proteins, advancing understanding of cellular motions such as vesicle transport and cell division, and applying single-molecule biophysical techniques to structural biology and energetics of these processes. His extensive academic experience includes numerous awards, leadership roles, and contributions to the scientific community in the fields of physiology, biophysics, and molecular motors.

Research topics

• Computer Science
• Biology
• Chemistry
• Physics
• Machine Learning
• Biophysics
• Genetics
• Materials science
• Biochemistry
• Optics
• Biological system
• Optoelectronics
• Cell biology
• Environmental science

Selected publications

• BPS2026 – Nanometer-scale RNA protein clusters (RPCs) as dynamic hubs for initiation-related dead-box helicases

  Biophysical Journal · 2026-02-01

  articleSenior author
  PublisherDOI

• A myosin hypertrophic cardiomyopathy mutation disrupts the super-relaxed state and boosts contractility by enhanced actin attachment

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-06-06 · 1 citations

  preprintOpen access

  Abstract Hypertrophic cardiomyopathy (HCM) is a leading cause of cardiac failure among individuals under 35. Many genetic mutations that cause HCM enhance ventricular systolic function, suggesting that these HCM mutations are hypercontractile. Among the most common causes of HCM are mutations in the gene MYH7, which encodes for β-cardiac myosin, the principal human ventricular myosin. Previous work has demonstrated that, for purified myosins, some MYH7 mutations are gain-of-function while others cause reduced function, so how they lead to enhanced contractility is not clear. Here, we have characterized the mechanics and kinetics of the severe HCM-causing mutation M493I. Motility assays demonstrate a 70% reduction of actin filament gliding velocities on M493I-coated surfaces relative to WT. This mutation slows ADP release from actomyosin·ADP 5-fold without affecting phosphate release or ATP binding. Yet it enhances steady-state ATPase V max 2-fold. Through single-molecule mechanical studies, we find that M493I myosin has a normal working stroke of 5 nm but a significantly prolonged actin attachment duration. Under isometric feedback, M493I myosins produce high, sustained force, with an actin detachment rate that is less sensitive to force than that of WT myosin. We also report direct measurement of the equilibrium state of the super-relaxed to disordered relaxed (SRX-DRX) regulatory transition and show its disruption in M493I, with a concomitant enhancement to actin attachment kinetics. Together, these data demonstrate that enhanced myosin binding from inhibition of myosin’s off state, combined with slow ADP release and enhanced force production, underlie the enhanced function and etiology of this HCM mutation. Significance Statement Hypertrophic cardiomyopathy (HCM) is a leading genetic cause of sudden cardiac death in young individuals. Although often described as a hypercontractile disease, the molecular basis for this remains unclear, especially for mutations with inhibitory effects in various in vitro assays. We show that the severe HCM mutation M493I in β-cardiac myosin slows ADP release yet enhances force output and actin attachment through multiple mechanisms, including disrupted autoinhibition via the super-relaxed state. Our findings unify seemingly contradictory biophysical changes into a coherent mechanistic model and support the hypothesis that increased myosin head availability, rather than enhanced individual kinetics alone, underlies HCM hypercontractility.

  PublisherOA PDFDOI

• Suppression of nonsense mutations by small, cyclic peptides

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-04-26

  preprintOpen access

  ABSTRACT Premature termination codons in mRNAs result from nonsense mutations and hinder the translation of full-length, functional proteins. Nonsense mutations cause numerous serious genetic diseases, including cystic fibrosis and Duchenne muscular dystrophy. Several small-molecule drugs have been reported that could potentially ameliorate these diseases by promoting translational readthrough at the premature termination codon. However, utilization of many of these molecules faces problems such as limited efficacy or high cellular toxicity. Using a selection strategy in Saccharomyces cerevisiae coupling suppression of endogenous nonsense mutations to cell survival, we identified ten readthrough-promoting cyclic peptides from a DNA-encoded library. The selected cyclic peptides suppress nonsense mutations in various reporter genes, and the candidates inducing the highest readthrough levels display no observable cytotoxicity in yeast. Mutational analysis of the most promising cyclic peptide demonstrate that most amino acid side chains contribute to the readthrough-stimulating activity. Importantly, this cyclic peptide appears to bind directly to the eukaryotic core translation machinery and promotes readthrough in vitro by interfering with ribosomal decoding. Our results suggest that small, cyclic peptides selected in vivo could represent a novel drug type to treat the many incurable human genetic diseases that are caused by nonsense mutations.

  PublisherOA PDFDOI

• Dynamics of β-cardiac myosin between the super-relaxed and disordered-relaxed states

  Journal of Biological Chemistry · 2025-03-19 · 15 citations

  articleOpen access

  The super-relaxed (SRX) state of myosin ATPase activity is critical for striated muscle function, and its dysregulation is linked to cardiomyopathies. It is unclear whether the SRX state exchanges readily with the disordered-relaxed (DRX) state and whether the SRX state directly corresponds to the folded back interacting-heads motif. Using recombinant β-cardiac heavy meromyosin and subfragment 1, which cannot form the interacting-heads motif, we show that the SRX and DRX populations transition at a rate substantially faster than the ATP turnover rate, dependent on myosin head-tail interactions. Some mutations which cause hypertrophic or dilated cardiomyopathies alter the SRX-DRX equilibrium, but not all mutations. The cardiac myosin inhibitor mavacamten slows nucleotide release by an equal factor for both heavy meromyosin and subfragment 1, thus only indirectly influencing the occupancy time of the SRX state. These findings suggest that purified myosins undergo rapid switching between SRX and DRX states, refining our understanding of cardiomyopathy mechanisms.

  PublisherOA PDFDOI

• S2Tag, a novel affinity tag for the capture and immobilization of coiled-coil proteins: application to the study of human β-cardiac myosin

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-05-02

  preprintOpen access

  Single molecule and ensemble motility assays are powerful tools for investigating myosin activity. A key requirement for the quality and reproducibility of the data obtained with these methods is the mode of attachment of myosin to assay surfaces. We previously characterized the ability of a monoclonal antibody (10F12.3) to tether skeletal muscle myosin to nitrocellulose coated glass. Here, we identify the 11 amino-acid epitope (S2Tag) recognized by 10F12.3 in the coiled-coil S2 domain of myosin. To test the transferability of S2Tag, we inserted it into a wild-type β-cardiac myosin construct (WT-βCM) and evaluated its mechanochemistry. WT-βCM immobilized via S2Tag robustly propelled actin filaments in gliding assays and showed single-molecule actin displacements and attachment kinetics by optical trapping. Thus, the antibody attachment is effective for ensemble and single molecule assays. We inserted the S2Tag into a βCM construct containing a penetrant mutation (S532P-βCM) that causes dilated cardiomyopathy. Inclusion of S2Tag enabled quantitative mixed-motor gliding filament assays with WT-βCM. The analysis shows the S532P mutation results in a 60% decrease in gliding speed, yet the motor seems to produce the same force as WT-βCM. Importantly, S2Tag is a useful new tool for affinity capture of alpha-helical coiled coil proteins.

  PublisherOA PDFDOI

• A myosin hypertrophic cardiomyopathy mutation disrupts the super-relaxed state and boosts contractility by enhanced actin attachment

  Proceedings of the National Academy of Sciences · 2025-12-24 · 3 citations

  articleOpen accessCorresponding

  Hypertrophic cardiomyopathy (HCM) is a leading cause of cardiac failure among individuals under 35. Many genetic mutations that cause HCM seem to enhance ventricular systolic function, suggesting that these HCM mutations are hypercontractile. Among the most common causes of HCM are mutations in the gene MYH7, which encodes for β-cardiac myosin, the principal human ventricular myosin. Previous work has demonstrated that, for purified myosins, some MYH7 mutations are gain-of-function while others cause reduced function, so how they lead to enhanced contractility is not clear. Here, we have characterized the mechanics and kinetics of the severe HCM-causing mutation M493I. Motility assays demonstrate a 70% reduction of actin filament gliding velocities on M493I-coated surfaces relative to wild type (WT). This mutation slows ADP release from actomyosin•ADP fivefold without affecting phosphate release or ATP binding. Yet it enhances steady-state ATPase V max twofold. Through single-molecule mechanical studies, we find that M493I myosin has a normal working stroke of 5 nm but a significantly prolonged actin attachment duration. Under isometric feedback, M493I myosins produce high, sustained force, with an actin detachment rate that is less sensitive to force than that of WT myosin. We also report direct measurement of the equilibrium state of the super-relaxed to disordered relaxed regulatory transition and show its disruption in M493I, with a concomitant enhancement to actin attachment kinetics. Together, these data demonstrate that enhanced myosin binding from inhibition of myosin’s off state, combined with slow ADP release and enhanced force production, underlie the enhanced function and etiology of this HCM mutation.

  PublisherOA PDFDOI

• BPS2025 - Dynamic switching of β-cardiac myosin in the super-relaxed and disordered-relaxed states tunes motor properties and is insensitive to mavacamten

  Biophysical Journal · 2025-02-01

  article
  PublisherDOI

• Single molecule optical trap studies on actomyosin elucidate cardiovascular disease mechanisms

  2025-09-16

  articleSenior author

  Heart failure due to aging, anoxic episodes and cardiomyopathies is a major health-care problem. We studied possible therapeutic interventions and several point mutations in the beta-cardiac myosin motor amino acid sequence using single molecule optical trapping technology to understand their puzzling mechanisms. Omecamtiv mecarbil (OM) ameliorates heart failure, even though it suppresses myosins mechanical working stroke by a cooperative activation of the thin actin-containing filaments in the sarcomere. R712L and M493I are mutations in the myosin amino acid sequence that cause hypertrophic cardiomyopathy. Their specific alterations in the mechanics and dynamics detectable in the optical trap help explain the etiology and effects of therapeutic interventions.

  PublisherDOI

• S2Tag, a novel affinity tag for the capture and immobilization of coiled-coil proteins: Application to the study of human β-cardiac myosin

  Journal of Biological Chemistry · 2025-09-29 · 2 citations

  articleOpen access

  Single-molecule and ensemble motility assays are powerful tools for investigating myosin activity. A key requirement for the quality and reproducibility of the data obtained with these methods is the mode of attachment of myosin to assay surfaces. We previously characterized the ability of a monoclonal antibody (10F12.3) to tether skeletal muscle myosin to nitrocellulose-coated glass. Here, we identify the 11 amino acid epitope (S2Tag) recognized by 10F12.3 in the coiled-coil S2 domain of myosin. To test the transferability of S2Tag, we inserted it into a wild-type β-cardiac myosin construct (WT-βCM) and evaluated its mechanochemistry. WT-βCM immobilized via S2Tag robustly propelled actin filaments in gliding assays and showed single-molecule actin displacements and attachment kinetics by optical trapping. Thus, the antibody attachment is effective for ensemble and single-molecule assays. We inserted the S2Tag into a βCM construct containing a penetrant mutation (S532P-βCM) that causes dilated cardiomyopathy. Inclusion of S2Tag enabled quantitative mixed-motor gliding filament assays with WT-βCM. The analysis shows the S532P mutation results in a 60% decrease in gliding speed, yet the motor seems to produce the same force as WT-βCM. Importantly, S2Tag is a useful new tool for affinity capture of alpha-helical coiled coil proteins.

  PublisherOA PDFDOI

• Characterization and structural basis for the brightness of mCLIFY: A novel monomeric and circularly permuted bright yellow fluorescent protein

  Biophysical Journal · 2025-05-22

  article
  PublisherDOI

Recent grants

• NIH Grant R01GM063205

  NIH · $1.3M · 2006

• MRI: Development of Simultaneous Single Molecule Fluorescence and Atomic Force Microscopy

  NSF · $710k · 2007–2010

• "Structural Dynamics of Molecular Motors and the Ribosome" The studies proposed will give basic information on gene expression, cellular development, and transport motor function in cell biology.

  NIH · $7.2M · 2016–2026

• NIH Grant R01AR042333

  NIH · $872k · 1998

• NIH Grant P01GM087253

  NIH · $27.0M · 2020

Frequent coauthors

• Arne Elofsson

  81 shared

• Lawrence Gowdstein

  National Institutes of Health

  81 shared

• Thomas Watson

  81 shared

• Charles C. Bailey

  Broad Institute

  81 shared

• Britt‐Marie Sjöberg

  Stockholm University

  81 shared

• Nicholas Gibson

  81 shared

• Christopher Godek

  National Institutes of Health

  81 shared

• Lennart Nilsson

  Karolinska Institutet

  81 shared

Labs

• Yale E. Goldman LabPI

Awards & honors

• Upjohn Achievement Award (1975)
• Research Fellowship, Muscular Dystrophy Association (1977-19…
• National Research Service Award, NIH (1977-1979)
• Research Career Development Award, NIH (1980-1985)
• Lindback Foundation Award for Distinguished Teaching (1989)